[go: up one dir, main page]

WO2024186790A1 - Méthodes pronostiques et thérapeutiques contre le cancer du poumon non à petites cellules - Google Patents

Méthodes pronostiques et thérapeutiques contre le cancer du poumon non à petites cellules Download PDF

Info

Publication number
WO2024186790A1
WO2024186790A1 PCT/US2024/018472 US2024018472W WO2024186790A1 WO 2024186790 A1 WO2024186790 A1 WO 2024186790A1 US 2024018472 W US2024018472 W US 2024018472W WO 2024186790 A1 WO2024186790 A1 WO 2024186790A1
Authority
WO
WIPO (PCT)
Prior art keywords
individual
gene signature
signature score
sample
expression level
Prior art date
Application number
PCT/US2024/018472
Other languages
English (en)
Inventor
Barzin Y. NABET
Katherine Marie NUTSCH
Namrata Srivastava PATIL
Charles Wan-Yuen TRAN
Thomas D. Wu
Karl Luke BANTA
Eugene Yu-Chuan CHIANG
Original Assignee
Genentech, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Genentech, Inc. filed Critical Genentech, Inc.
Publication of WO2024186790A1 publication Critical patent/WO2024186790A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • Non-small cell lung cancer is the predominant subtype of lung cancer, accounting for approximately 80%-85% of all cases. For advanced disease, the overall five-year survival rate is 2%-4%.
  • NSCLC Non-small cell lung cancer
  • PD-1/PD-L1 Programmed cell death-1/programmed cell death ligand-1
  • TIGIT T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain.
  • the invention provides a method of identifying an individual having a non-small cell lung cancer (NSCLC) who may benefit from a treatment comprising atezolizumab and tiragolumab, the method comprising detecting an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in a sample from the individual, wherein an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 that is at or above a reference expression level of CCL5, CXCR3, CCR7, or CXCR6 identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • NSCLC non-small cell lung cancer
  • the invention provides a method for selecting a therapy for an individual having a NSCLC, the method comprising detecting an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in a sample from the individual, wherein an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 that is at or above a reference expression level of CCL5, CXCR3, CCR7, or CXCR6 identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the individual has an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in the sample that is at or above a reference expression level of CCL5, CXCR3, CCR7, or CXCR6, and the method further comprises administering to the individual an effective amount of atezolizumab and tiragolumab.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising (a) detecting an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in a sample from the individual, wherein the expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 is at or above a reference expression level of CCL5, CXCR3, CCR7, or CXCR6 and thereby identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab; and (b) administering an effective amount of atezolizumab and tiragolumab to the individual.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising administering atezolizumab and tiragolumab to the individual, wherein the individual has been determined to have an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 that is at or above a reference expression level of CCL5, CXCR3, CCR7, or CXCR6, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the benefit is a clinical response.
  • the clinical response is a complete response (CR) or a partial response (PR).
  • the individual has an expression level of one or more of CCL5, CXCR3, and CCR7 in the sample that is at or above a reference expression level of CCL5, CXCR3, or CCR7 and the benefit is an increase in overall survival (OS) hazard ratio (HR).
  • the individual has an expression level of one or more of CCL5, CXCR3, and CXCR6 in the sample that is at or above a reference expression level of CCL5, CXCR3, or CXCR6 and the benefit is an increase in overall survival (OS).
  • the reference expression level of CCL5, CXCR3, or CXCR6 is a pre-assigned expression level.
  • the reference expression level of CCL5, CXCR3, or CXCR6 is an expression level in a reference population. In some aspects, the expression level in the reference population is the median expression level of CCL5, CXCR3, or CXCR6 in the reference population. In some aspects, the reference population is a population of individuals having the NSCLC.
  • the invention provides a method of identifying an individual having a NSCLC who may benefit from a treatment comprising atezolizumab and tiragolumab, the method comprising detecting an expression level of each of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score that is at or above a reference gene signature score identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the individual has a gene signature score in the sample that is at or above a reference gene signature score, and the method further comprises administering to the individual an effective amount of atezolizumab and tiragolumab.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising (a) detecting an expression level of each of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein the gene signature score is at or above a reference gene signature score and thereby identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab; and (b) administering an effective amount of atezolizumab and tiragolumab to the individual.
  • the method comprises further detecting the expression level of CCR7 in the sample from the individual.
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.
  • the expression level of CCR7 has been detected in the sample from the individual.
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.
  • the benefit is a clinical response.
  • the clinical response is a CR or a PR.
  • the benefit is an increase in OS HR.
  • the benefit is an increase in OS.
  • the reference gene signature score is a pre-assigned gene signature score. In some aspects, the reference gene signature score is a gene signature score in a reference population. In some aspects, the gene signature score in the reference population is the median gene signature score based on the expression level of each of CCL5, CXCR3, and CXCR6 in the reference population. In some aspects, the reference population is a population of individuals having the NSCLC.
  • the invention provides a method of identifying an individual having a NSCLC who may benefit from a treatment comprising atezolizumab and tiragolumab, the method comprising: (a) detecting an expression level of each of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X in a sample from the individual and determining a Ccr7.2 gene signature score therefrom; (b) detecting an expression level of each of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB in a sample from the individual and determining a Ccr7.3 gene signature score therefrom; PATENT Attorney
  • the invention provides a method for selecting a therapy for an individual having a NSCLC, the method comprising: (a) detecting an expression level of each of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X in a sample from the individual and determining a Ccr7.2 gene signature score therefrom; (b) detecting an expression level of each of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB in a sample from the individual and determining a Ccr7.3 gene signature score therefrom; (c) detecting an expression level of each of CXCR6, CKB, GIMAP5, ID
  • the individual has (i) a Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, or Mitotic gene signature score in the sample that is at or above a reference gene signature score or (ii) a Cytotox.2 or Cytotox.4 gene signature score that is below a reference gene signature score, and the method further comprises administering to the individual an effective amount of atezolizumab and tiragolumab.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising: (i) (a) detecting an expression level of each of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X in a sample from the individual and determining a Ccr7.2 gene signature score therefrom, wherein the gene signature score is at or above a reference gene signature score and thereby identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab; (b) detecting an expression level of each of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and
  • the invention provides a method of treating an individual having a NSCLC, the method comprising administering atezolizumab and tiragolumab to the individual, wherein the individual has been determined to have: (a) a Ccr7.2 gene signature score based on an expression level of each of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X in a sample from the individual that is at or above a reference Ccr7.2 gene signature score; (b) a Ccr7.3 gene signature based on an expression level of each of DAPL1, CCR7, SMC4, RGCC, MXD4, CD8A, TCF7, ITGAE, RGS10, ZNRF1, CHD3, CD52, DDIT4, LEF1, IZUMO1R, INPP4B, and RFLNB in
  • the gene signature score is an average of the expression levels of the members of the gene signature in the sample from the individual.
  • the individual has a Ccr7.3, Cxcr3, or Ccl5.1 gene signature score in the sample that is at or above a reference gene signature score and the benefit is a clinical response.
  • the clinical response is a CR or a PR.
  • the individual has (i) a Ccr7.2, Cxcr3, Ifit, or Mitotic gene signature score in the sample that is at or above a reference gene signature score or (ii) a Cytotox.2 or Cytotox.4 gene signature score that is below a reference gene signature score and the benefit is an increase in OS HR.
  • the individual has a Ccr7.2, Ccr7.3, or Cxcr3 gene signature score in the sample that is at or above a reference gene signature score and the benefit is an increase in OS.
  • the reference gene signature score is a pre-assigned gene signature score.
  • the reference gene signature score is a gene signature score in a reference population.
  • the gene signature score in the reference population is the median Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox.2, or Cytotox.4 gene signature score in the reference population.
  • the reference population is a population of individuals having the NSCLC.
  • the invention provides a method of identifying an individual having a NSCLC who may benefit from a treatment comprising atezolizumab, the method comprising detecting an expression level of each of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score that is at or above a reference gene PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO signature score identifies the individual as one who may benefit from a treatment comprising atezolizumab.
  • the invention provides a method for selecting a therapy for an individual having a NSCLC, the method comprising detecting an expression level of each of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score that is at or above a reference gene signature score identifies the individual as one who may benefit from a treatment comprising atezolizumab.
  • the individual has a gene signature score in the sample that is at or above a reference gene signature score, and the method further comprises administering to the individual an effective amount of atezolizumab.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising (a) detecting an expression level of each of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein the gene signature score is at or above a reference gene signature score and thereby identifies the individual as one who may benefit from a treatment comprising atezolizumab; and (b) administering an effective amount of atezolizumab to the individual.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising administering atezolizumab to the individual, wherein the individual has been determined to have a gene signature score that is at or above a reference gene signature score, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab, and wherein the gene signature score is based on the expression level of each of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, and CXCR6 in the sample from the individual.
  • the method comprises further detecting the expression level of CCR7 in the sample from the individual.
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual. In some aspects, the expression level of CCR7 has been detected in the sample from the individual. In some aspects, the gene signature score is an average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual. In some aspects, the benefit is an increase in progression-free survival (PFS) or OS. In some aspects, the reference gene signature score is a pre-assigned gene signature score. In some aspects, the reference gene signature score is a gene signature score in a reference population.
  • the gene signature score in the reference population is the median gene signature score based on the expression level of each of CCL5, CXCR3, and CXCR6 in the reference population.
  • the reference population is a population of individuals having the NSCLC.
  • the treatment comprising atezolizumab is atezolizumab monotherapy.
  • the invention provides use of atezolizumab and/or tiragolumab in the manufacture of a medicament for the treatment of an individual having a NSCLC, wherein the individual has been determined to have an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO a sample from the individual that is at or above a reference expression level of CCL5, CXCR3, CCR7, or CXCR6, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the benefit is a clinical response.
  • the clinical response is a complete response (CR) or a partial response (PR).
  • the individual has been determined to have an expression level of one or more of CCL5, CXCR3, and CCR7 in the sample that is at or above a reference expression level of CCL5, CXCR3, or CCR7 and the benefit is an increase in overall survival (OS) hazard ratio (HR).
  • the individual has been determined to have an expression level of one or more of CCL5, CXCR3, and CXCR6 in the sample that is at or above a reference expression level of CCL5, CXCR3, or CXCR6 and the benefit is an increase in overall survival (OS).
  • the reference expression level of CCL5, CXCR3, or CXCR6 is a pre-assigned expression level. In some aspects, the reference expression level of CCL5, CXCR3, or CXCR6 is an expression level in a reference population. In some aspects, the expression level in the reference population is the median expression level of CCL5, CXCR3, or CXCR6 in the reference population. In some aspects, the reference population is a population of individuals having the NSCLC.
  • the invention provides use of atezolizumab and/or tiragolumab in the manufacture of a medicament for the treatment of an individual having a NSCLC, wherein the individual has been determined to have a gene signature score that is at or above a reference gene signature score, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab, wherein the gene signature score is based on the expression level of each of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, and CXCR6 in the sample from the individual.
  • the expression level of CCR7 has been detected in the sample from the individual.
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.
  • the benefit is a clinical response.
  • the clinical response is a CR or a PR.
  • the benefit is an increase in OS HR.
  • the benefit is an increase in OS.
  • the reference gene signature score is a pre-assigned gene signature score.
  • the reference gene signature score is a gene signature score in a reference population.
  • the gene signature score in the reference population is the median gene signature score based on the expression level of each of CCL5, CXCR3, and CXCR6 in the reference population.
  • the reference population is a population of individuals having the NSCLC.
  • the invention provides use of atezolizumab and/or tiragolumab in the manufacture of a medicament for the treatment of an individual having a NSCLC, wherein the individual has been determined to have: PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO (i) (a) a Ccr7.2 gene signature score that is at or above a reference gene signature score, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab, wherein the gene signature score is based on the expression level of each of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29,
  • the gene signature score is an average of the expression levels of the members of the gene signature in the sample from the individual.
  • the individual has been determined to have a Ccr7.3, Cxcr3, or Ccl5.1 gene signature score in the sample that is at or above a reference gene signature score and the benefit is a clinical response.
  • the clinical response is a CR or a PR.
  • the individual has been determined to have (i) a Ccr7.2, Cxcr3, Ifit, or Mitotic gene signature score in the sample that is at or above a reference gene signature score or (ii) a Cytotox.2 or Cytotox.4 gene signature score that is below a reference gene signature score and the benefit is an increase in OS HR.
  • the individual has been determined to have a Ccr7.2, Ccr7.3, or Cxcr3 gene signature score in the sample that is at or above a reference gene signature score and the benefit is an increase in OS.
  • the reference gene signature score is a pre-assigned gene signature score.
  • the reference gene signature score is a gene signature score in a reference population.
  • the gene signature score in the reference population is the median Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox.2, or Cytotox.4 gene signature score in the reference population.
  • the reference population is a population of individuals having the NSCLC.
  • the invention provides use of atezolizumab in the manufacture of a medicament for the treatment of an individual having a NSCLC, wherein the individual has been determined to have a gene signature score that is at or above a reference gene signature score, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab, wherein the gene signature score is based on the expression level of each of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, and CXCR6 in the sample from the individual.
  • the expression level of CCR7 has been detected in the sample from the individual.
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.
  • the benefit is an increase in progression-free survival (PFS) or OS.
  • the reference gene signature score is a pre-assigned gene signature score.
  • the reference gene signature score is a gene signature score in a reference population.
  • the gene signature score in the reference population is the median gene signature score based on the expression level of each of CCL5, CXCR3, and CXCR6 in the reference population.
  • the reference population is a population of individuals having the NSCLC.
  • the treatment comprising atezolizumab is atezolizumab monotherapy.
  • the invention provides atezolizumab and/or tiragolumab for use in treating an individual having a NSCLC, wherein the individual has been determined to have an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in a sample from the individual that is at or above a PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO reference expression level of CCL5, CXCR3, CCR7, or CXCR6, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the benefit is a clinical response.
  • the clinical response is a complete response (CR) or a partial response (PR).
  • the individual has been determined to have an expression level of one or more of CCL5, CXCR3, and CCR7 in the sample that is at or above a reference expression level of CCL5, CXCR3, or CCR7 and the benefit is an increase in overall survival (OS) hazard ratio (HR).
  • the individual has been determined to have an expression level of one or more of CCL5, CXCR3, and CXCR6 in the sample that is at or above a reference expression level of CCL5, CXCR3, or CXCR6 and the benefit is an increase in overall survival (OS).
  • the reference expression level of CCL5, CXCR3, or CXCR6 is a pre-assigned expression level. In some aspects, the reference expression level of CCL5, CXCR3, or CXCR6 is an expression level in a reference population. In some aspects, the expression level in the reference population is the median expression level of CCL5, CXCR3, or CXCR6 in the reference population. In some aspects, the reference population is a population of individuals having the NSCLC.
  • the invention provides atezolizumab and/or tiragolumab for use in treating an individual having a NSCLC, wherein the individual has been determined to have a gene signature score that is at or above a reference gene signature score, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab, wherein the gene signature score is based on the expression level of each of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, and CXCR6 in the sample from the individual.
  • the expression level of CCR7 has been detected in the sample from the individual.
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.
  • the benefit is a clinical response.
  • the clinical response is a CR or a PR.
  • the benefit is an increase in OS HR.
  • the benefit is an increase in OS.
  • the reference gene signature score is a pre-assigned gene signature score.
  • the reference gene signature score is a gene signature score in a reference population.
  • the gene signature score in the reference population is the median gene signature score based on the expression level of each of CCL5, CXCR3, and CXCR6 in the reference population.
  • the reference population is a population of individuals having the NSCLC.
  • the invention provides atezolizumab and/or tiragolumab for use in treating an individual having a NSCLC, wherein the individual has been determined to have: PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO (i) (a) a Ccr7.2 gene signature score that is at or above a reference gene signature score, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab, wherein the gene signature score is based on the expression level of each of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X detected in a sample from the individual; (b) a Ccr
  • the individual has been determined to have a Ccr7.2, Ccr7.3, or Cxcr3 gene signature score in the sample that is at or above a reference gene signature score and the benefit is an increase in OS.
  • the reference gene signature score is a pre-assigned gene signature score.
  • the reference gene signature score is a gene signature score in a reference population.
  • the gene signature score in the reference population is the median Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox.2, or Cytotox.4 gene signature score in the reference population.
  • the reference population is a population of individuals having the NSCLC.
  • the invention provides atezolizumab for use in treating an individual having a NSCLC, wherein the individual has been determined to have a gene signature score that is at or above a reference gene signature score, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab, wherein the gene signature score is based on the expression level of each of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, and CXCR6 in the sample from the individual.
  • the expression level of CCR7 has been detected in the sample from the individual.
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.
  • the benefit is an increase in progression-free survival (PFS) or OS.
  • the reference gene signature score is a pre-assigned gene signature score.
  • the reference gene signature score is a gene signature score in a reference population.
  • the gene signature score in the reference population is the median gene signature score based on the expression level of each of CCL5, CXCR3, and CXCR6 in the reference population.
  • the reference population is a population of individuals having the NSCLC.
  • the treatment comprising atezolizumab is atezolizumab monotherapy.
  • the expression level is a nucleic acid expression level or a protein expression level.
  • PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO the expression level is a nucleic acid expression level.
  • the nucleic acid expression level is determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, ISH, or a combination thereof.
  • the nucleic acid expression level is an mRNA expression level.
  • the mRNA expression level is determined by RNA-seq.
  • the expression level is a protein expression level.
  • the protein expression level is determined by mass spectrometry.
  • the sample is obtained from the individual prior to treatment with atezolizumab and/or tiragolumab.
  • the sample is a tissue sample, a tumor sample, a blood sample, a plasma sample, a serum sample, or a combination thereof.
  • the sample is a tissue sample.
  • the tissue sample is a tumor tissue sample.
  • the tumor tissue sample is a biopsy.
  • the tissue sample is a tumor draining lymph node (dLN) sample.
  • the sample is a blood sample.
  • the sample is an archival sample, a fresh sample, or a frozen sample.
  • the individual has a PD-L1-positive NSCLC.
  • the PD-L1- positive NSCLC has been determined to have a PD-L1-positive tumor cell fraction by an immunohistochemical (IHC) assay.
  • the PD-L1-positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8.
  • the individual is a human. In some aspects, the individual has not previously been treated for NSCLC.
  • FIG.1B is a set of bar graphs showing the frequency of CD8 + T cells with positive staining for the gp70-specific tetramer in dLN (left panel); the number of CD8 + T cells with positive staining for the gp70- specific tetramer in blood (right panel); and the frequency of CD8 + T cells with positive staining for the gp70-specific tetramer in tumor (right panel) in BALB/c CT26 tumor model mice treated with an isotype control, anti-PD-L1, anti-TIGIT, and/or FTY720. p-values are indicated where differences between two groups were determined by two-way unpaired Student’s t-test to be statistically significant.
  • FIG.1C is a bar graph showing quantitation of CD8 + T cells producing IFN-g and TNF-a as a percentage of total CD8 + tumor-infiltrating lymphocytes (TILs) in BALB/c CT26 tumor model mice treated with an isotype control, anti-PD-L1, anti-TIGIT, and/or FTY720.
  • FIG.1D is a set of graphs showing tumor volume (mm 3 ) (log2 scale) over time in BALB/c mice that were inoculated subcutaneously with syngeneic CT26 tumor cells, treated with an isotype control or the combination of anti-PD-L1 and anti-TIGIT antibodies, and treated with FTY720 at day 0, one day prior to initiation of therapy, or on day 7 after one week of therapy (delayed FTY720).
  • Grouped analysis left panel
  • right panel Tumor growth efficacy study is representative of three independent experiments.
  • FIG.2A is a Uniform Manifold Approximation and Projection (UMAP) showing 174,514 CD8 + T cells isolated from tumor, dLN, and blood of CT26 tumor model mice shaded by cluster.
  • FIG.2B is a heatmap showing the relative average expression of selected marker genes associated with CD8 + T cell phenotype, function, or differentiation state in each cluster identified in the UMAP shown in Fig.2A.
  • FIG.2C is a set of stacked bar graphs of CD8 + T cell cluster composition in lymph nodes and blood under the indicated treatment condition.
  • FIG.2D is a set of stacked bar graphs of CD8 + T cell cluster composition in blood (Day 7) and tumor under the indicated treatment condition.
  • an open bar denotes singletons
  • a solid bar denotes numbers for clones with less than 100 cells
  • a hatched bar denotes numbers for clones with 100 or more cells.
  • FIG.3A is an image showing relative clone sizes projected on the CD8 + T cell UMAP shown in Fig.2A.
  • FIG.3D is a set of scatterplots showing primary clusters of each individual clonotype in dLN (upper panels) or tumor (lower panels). Shade of circles denote cluster designation. Size of circles is representative of clonotype numbers detected in blood at day 7.
  • FIG.3E is a set of scatterplots showing gp70 specificity and ADT count for individual clones.
  • FIG.3F is a set of stacked bar graphs showing the cluster composition of the top 50 largest clones in tumor with matching clonotypes, based on identical TCR usage, in dLN and blood, in absolute numbers. Cluster identity is indicated by shade.
  • FIG.4A is a set of UMAPs showing a cluster co-occurrence analysis in dLN (lymph), blood, and tumor samples from CT26 tumor model mice treated with a control anti-gp120 treatment.
  • Lines within UMAPs denote co-occurrence between different clusters within the indicated tissue.
  • Lines between PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO UMAPs denote co-occurrence between the same cluster in different tissues.
  • Thickness of line denotes relative strength of co-occurrence, with thickest lines indicating strongest co-occurrence. For lines between tissues, shade of the line indicates the cluster.
  • FIG.4B is a set of UMAPs showing a cluster co-occurrence analysis in dLN (lymph), blood, and tumor samples from CT26 tumor model mice treated with an anti-PD-L1 antibody.
  • FIG.4C is a set of UMAPs showing a cluster co-occurrence analysis in dLN (lymph), blood, and tumor samples from CT26 tumor model mice treated with an anti-TIGIT antibody.
  • FIG.4D is a set of UMAPs showing a cluster co-occurrence analysis in dLN (lymph), blood, and tumor samples from CT26 tumor model mice treated with an anti-TIGIT antibody and an anti-PD-L1 antibody.
  • FIG.4E is a set of UMAPs showing a cluster co-occurrence analysis in dLN (lymph), blood, and tumor samples from CT26 tumor model mice treated with an anti-TIGIT antibody, an anti-PD-L1 antibody, and FTY720.
  • FIG.5A is a plot showing the proportion of gp70 + CD8 + T cells from dLN of CT26 tumor-bearing mice treated with anti-PD-L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT with or without FTY720 (FTY) that expressed CD226. p-values are indicated where differences between two groups were determined by two-way unpaired Student’s t-test to be statistically significant.
  • FIG.5B is a set of plots showing the proportion of CD226 + (left panel) or CD226- (right panel) gp70 + CD8 + T cells from dLN of CT26 tumor-bearing mice treated with anti-PD-L1, anti-TIGIT, or anti-PD- L1 + anti-TIGIT with or without FTY720 (FTY) that expressed Ki67.
  • FIG.5C is a set of plots showing the proportion of CD226 + (left panel) or CD226- (right panel) gp70 + CD8 + T cells from dLN of CT26 tumor-bearing mice treated with anti-PD-L1, anti-TIGIT, or anti-PD- L1 + anti-TIGIT with or without FTY720 (FTY) that had a na ⁇ ve phenotype.
  • FIG.5D is a set of plots showing the proportion of CD226 + (left panel) or CD226- (right panel) gp70 + CD8 + T cells from dLN of CT26 tumor-bearing mice treated with anti-PD-L1, anti-TIGIT, or anti-PD- L1 + anti-TIGIT with or without FTY720 (FTY) that had a cytotoxic CD8 + T effector / memory cell (Teff/Tem) phenotype.
  • FTY720 FTY720
  • FIG.5E is a set of plots showing the proportion of CD226 + (left panel) or CD226- (right panel) gp70 + CD8 + T cells from dLN of CT26 tumor-bearing mice treated with anti-PD-L1, anti-TIGIT, or anti-PD- L1 + anti-TIGIT with or without FTY720 (FTY) that expressed PD-1.
  • FTY720 FTY720
  • FIG.5F is a set of plots showing the proportion of CD226 + (left panel) or CD226- (right panel) gp70 + CD8 + T cells from dLN of CT26 tumor-bearing mice treated with anti-PD-L1, anti-TIGIT, or anti-PD- L1 + anti-TIGIT with or without FTY720 (FTY) that expressed TCF1 and Tim3.
  • FIG.5G is a set of plots showing the proportion of CD226 + (left panel) or CD226- (right panel) gp70 + CD8 + T cells from dLN of CT26 tumor-bearing mice treated with anti-PD-L1, anti-TIGIT, or anti-PD- L1 + anti-TIGIT with or without FTY720 (FTY) that expressed Tox.
  • FIG.5H is a plot showing the proportion of gp70 + CD8 + T cells from tumor tissue of CT26 tumor- bearing mice treated with anti-PD-L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT with or without FTY720 (FTY) that expressed CD226.
  • FIG.5I is a set of plots showing the proportion of CD226 + (left panel) or CD226- (right panel) gp70 + CD8 + T cells from tumor tissue of CT26 tumor-bearing mice treated with anti-PD-L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT with or without FTY720 (FTY) that expressed Ki67.
  • FIG.5J is a set of plots showing the proportion of CD226 + (left panel) or CD226- (right panel) gp70 + CD8 + T cells from tumor tissue of CT26 tumor-bearing mice treated with anti-PD-L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT with or without FTY720 (FTY) that expressed TCF1 and Tim3.
  • FTY720 FTY720
  • FIG.5K is a set of plots showing the proportion of CD226 + (left panel) or CD226- (right panel) gp70 + CD8 + T cells from tumor tissue of CT26 tumor-bearing mice treated with anti-PD-L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT with or without FTY720 (FTY) that expressed Tox.
  • FIG.5L is a set of plots showing the proportion of dLN (left panel) or tumor (right panel) gp70 + CD8 + T cells from CT26 tumor-bearing mice treated with anti-PD-L1 + anti-TIGIT, anti-PD-L1 + anti- TIGIT + anti-CD226, or a control that expressed TCF1 and Tim3.
  • FIG.5M is a set of plots showing the proportion of dLN (left panel) or tumor (right panel) gp70 + CD8 + T cells from CT26 tumor-bearing mice treated with anti-PD-L1 + anti-TIGIT, anti-PD-L1 + anti- TIGIT + anti-CD226, or a control that expressed Tox.
  • FIG.6A is a set of box-and-whisker plots showing associations between levels of the indicated human gene signature scores in baseline tumor bulk RNA-seq samples from the Phase 2 CITYSCAPE non-small cell lung cancer (NSCLC) trial and clinical response to tiragolumab plus atezolizumab.
  • NSCLC Phase 2 CITYSCAPE non-small cell lung cancer
  • FIG.6B is a set of box-and-whisker plots showing associations between expression levels of the indicated individual human genes in baseline tumor bulk RNA-seq samples from Phase 2 CITYSCAPE NSCLC trial patients that were treated with tiragolumab plus atezolizumab or placebo plus atezolizumab, separated on the basis of clinical response.
  • FIG.6C is a forest plot showing association of high or low expression of indicated individual human gene with overall survival (OS) hazard ratio (HR) in tiragolumab plus atezolizumab (T+A) or placebo plus atezolizumab (P+A) treatment groups. Mean HR with 95% confidence intervals and p- values are shown.
  • FIG.6D is a set of Kaplan-Meier (K-M) curves showing the probability of OS in P+A or T+A treatment groups dichotomized on the basis of high or low expression of indicated gene. p-value is from a log-rank test with the null hypothesis that there is no difference between the groups.
  • K-M Kaplan-Meier
  • FIG.6E is a set of box-and-whisker plots showing a gene score calculated using the average expression of the CD8 gene panel comprised of CCR7, CXCR3, CXCR6 and CCL5 (top) or CXCR3, CXCR6 and CCL5 (bottom) in tumor bulk RNA-seq samples from patients treated with tiragolumab plus atezolizumab separated on the basis of clinical response.
  • FIG.6F is a forest plot showing association of high or low expression of the indicated composite gene scores with OS HR in T+A or P+A treatment groups. Mean HR with 95% confidence intervals and p- values are shown.
  • FIG.6G is a set of K-M curves showing the probability of OS in P+A or T+A treatment groups dichotomized on the basis of high or low composite gene score. p-value is from a log-rank test with the null hypothesis that there is no difference between the groups.
  • FIG.7A is a set of diagrams showing experimental schema for tumor growth and pharmacodynamic (PD) analysis for the CT26 and EO771 studies (left); delayed FTY720 treatment in the CT26 model (middle); and multi-omic analysis of T cells in the CT26 tumor model (right).
  • PD tumor growth and pharmacodynamic
  • FIG.7B is a set of graphs showing tumor volume (mm 3 ) (log2 scale) over time in C57BL/6 mice that were inoculated in mammary fat pad with EO771 tumor cells, treated with an isotype control anti-PD- L1, anti-TIGIT, or the combination of anti-PD-L1 and anti-TIGIT antibodies, with or without FTY720.
  • FIG.7C is a set of plots showing the total numbers of CD8 + T cells, CD4 + T cells, or Tregs in dLN (top panels) or tumor (bottom panels) of CT26 tumor-bearing mice treated with isotype control, anti-PD- L1, anti-TIGIT, or the combination, with or without FTY720.
  • n 5 mice per group, mean ⁇ s.d. are represented by bars and whiskers. Data are representative of three independent experiments.
  • FIG.7D is a set of bar graphs showing the frequency of CD8 + T cells that had positive staining for the gp70-specific tetramer in dLN (left panel); the number of CD8 + T cells with positive staining for the gp70-specific tetramer in blood (right panel); and the frequency of CD8 + T cells with positive staining for the gp70-specific tetramer in tumor (right panel) in BALB/c CT26 tumor model mice treated with isotype control, anti-PD-L1 (denoted as aPDL1 or aP), anti-TIGIT (denoted as aTIGIT or aT), or the combination of anti-PD-L1 and anti-TIGIT antibodies, with or without FTY720.
  • isotype control anti-PD-L1 (denoted as aPDL1 or aP), anti-TIGIT (denoted as aTIGIT or aT), or the combination of anti-PD-L1
  • Fig.7E is a bar graph showing quantitation of CD8 + T cells producing IFN-g and TNF-a as a percentage of total CD8 + tumor-infiltrating lymphocytes (TILs) in BALB/c CT26 tumor model mice treated with an isotype control, anti-PD-L1, anti-TIGIT, and/or FTY720.
  • TILs tumor-infiltrating lymphocytes
  • FIG.8A is a set of representative dot plots showing IFN-g and TNF-a intracellular staining in CD8 + T cells from tumor.
  • FIG.8B is a set of representative dot plots for CD226 and PD-1 co-expression on CD8 + T cells in dLN (top) and for Tim3 and PD-1 co-expression on CD8 + T cells in dLN (bottom).
  • FIG.8C is a set of representative dot plots for CD226 and LAG3 co-expression on CD8 + T cells in tumor (top) and for Tim3 and PD-1 co-expression on CD8 + T cells in tumor (bottom).
  • FIG.8D is a set of representative dot plots for TCF1 and Tox co-expression on CD8 + T cells in dLN (top) or in tumor (bottom).
  • FIG.8E is a set of representative dot plots for SLAMF6 and TCF1 co-expression on CD8 + T cells in tumor.
  • FIG.8F is a set of representative dot plots for CD226 and gp70 tetramer co-expression on CD8 + T cells in dLN (top) or tumor (middle), or gp70 tetramer staining on CD8 + T cells in blood (bottom).
  • FIG.9A is a set of images showing T cell clusters representing CD8 + T cells, CD4 + T cells, and regulatory T cells in 305,908 total T cells pooled from CT26 tumor, dLN, and blood from 31 mice.
  • 10 CD8 + T cell clusters (Ccl5-1, Ribo-2, Ccl5-3, CD8-4, CD8-5, Mitotic-9, Mitotic-12, Xcl1-13, Ifn-15, and Ly6a-16), four conventional CD4 + T cell clusters (CD40Ig-0, CD40Ig-7, Vim-11, and Stat1-14), two regulatory T (Treg) cell clusters (Treg-6, Treg-8), three clusters of mitotic cells (Mitotic-9, Mitotic-12, and Mitotic-20), two clusters of dying cells (Dying-10 and Dying-17), and several clusters with no clear phenotype (Gxp1-19, CD74-18, and CD74-21) were classified.
  • FIG.9B is a set of images showing CITE-seq relative expression levels for the indicated markers projected on a UMAP.
  • FIG.10A is a set of images showing relative expression levels of the indicated markers, as measured by CITE-seq, projected on UMAPs comprised of CD8 + T cells from CT26 tumor, dLN, and blood.
  • FIG.10B is a heatmap showing relative CITE-seq marker expression levels in the indicated tissues under various treatment conditions.
  • FIG.11A is a set of heatmaps showing cross-labelling of CD8 + T cell clusters (rows) to reference gene signatures (columns), taken from the analyses of Huang et al., Cell, 185: 1-18, 2022; Deak et al., Nature, 610: 173–181, 2022); Hashimoto et al., Nature, 610: 173–181, 2022; and Daniel et al., Nat Immunol, 23: 1614-1627, 2022, with intensities indicating normalized frequency.
  • FIG.11B is a set of UMAPs showing cluster composition in dLN (lymph), tumor, and blood from CT26 tumor-bearing mice treated with isotype control, anti-PD-L1, anti-TIGIT, combination, or combination with FTY720.
  • FIG.12A is a set of scatterplots showing primary clusters of each of the indicated individual clonotypes in dLN and blood at day 7. The shade of the circles denotes cluster designation as shown in Fig.3D.
  • FIG.12B is a set of stacked bar graphs showing cluster composition for the 50 largest clonotypes from tumor (upper panels), lymph node (middle panels), or blood at day 7 (lower panels) of CT26 tumor- bearing mice treated with isotype control, anti-PD-L1, anti-TIGIT, combination, or combination with FTY720, shown as absolute numbers. Cluster identity is indicated by shade.
  • FIG.13A is a heatmap showing relative co-occurrence relationships within or between dLN, blood, and tumors for CD8 + T cells clusters from CT26 tumor-bearing mice. Greater intensity of co- occurrence between two clusters indicates greater similarity, indicative of shared differentiation trajectory.
  • FIG.13B is a heatmap showing clusters defined using metadata from Li et al., J Exp Med, 219: e20210749, 2022, wherein CD8T1 are likely na ⁇ ve, CD8T2 has Tscm/memory properties, CD8T4 has activated effector cell properties, and CD8T5 has an exhausted phenotype.
  • CD8T1 and CD8T2 were described as T cells that recently entered the tumor, while CD8T4 and CD8T5 were cells resident in tumor. CD8T2 also have the capacity to recirculate from tumor to dLN.
  • FIG.14A is a set of charts showing the frequencies of CD8 + T cells in dLN (left) or tumor (right) as a percentage of CD45 + cells in mice with established EO771 tumors that were treated with an isotype control Ab or anti-TIGIT combined with anti-PD-L1.
  • dLN and tumors were collected on day 7 post- treatment for phenotypic characterization of CD8 + T cells by flow cytometry.
  • n 4 per group; mean and s.d. are shown as bar and whiskers; data are representative of one of two independent experiments. p- values are indicated where differences were determined by unpaired t-test to be statistically significant.
  • FIG.14B is a set of charts showing the frequencies of CD8 + T cells expressing CD226 in dLN (left) or tumor (right) as a percentage of CD45 + cells in mice with established EO771 tumors that were treated with an isotype control Ab or anti-TIGIT combined with anti-PD-L1.
  • dLN and tumors were collected on day 7 post-treatment for phenotypic characterization of CD8 + T cells by flow cytometry.
  • n 4 per group; mean and s.d. are shown as bar and whiskers; data are representative of one of two independent experiments. p-values are indicated where differences were determined by unpaired t-test to be statistically significant.
  • FIG.14C is a set of charts showing the frequencies of CD8 + T cells positively stained with tetramer against EO771-specific antigen p15E in dLN (left) or tumor (right) as a percentage of CD45 + cells in mice with established EO771 tumors that were treated with an isotype control Ab or anti-TIGIT combined with anti-PD-L1.
  • dLN and tumors were collected on day 7 post-treatment for phenotypic characterization of CD8 + T cells by flow cytometry.
  • n 4 per group; mean and s.d. are shown as bar and whiskers; data are representative of one of two independent experiments. p-values are indicated where differences were determined by unpaired t-test to be statistically significant.
  • FIG.14D is a set of charts showing the frequencies of p15E + CD8 + T cells expressing CD226 in dLN (left) or tumor (right) as a percentage of CD45 + cells in mice with established EO771 tumors that were treated with an isotype control Ab or anti-TIGIT combined with anti-PD-L1.
  • dLN and tumors were collected on day 7 post-treatment for phenotypic characterization of CD8 + T cells by flow cytometry.
  • n 4 per group; mean and s.d. are shown as bar and whiskers; data are representative of one of two independent experiments. p-values are indicated where differences were determined by unpaired t-test to be statistically significant.
  • FIG.14E is a set of charts showing the frequencies of CD226 + (left) or CD226- (right) p15E + CD8 + Teff/Tem cells co-expressing TCF1 and Tim3 in dLN (left) or tumor (right) as a percentage of CD45 + cells in mice with established EO771 tumors that were treated with an isotype control Ab or anti-TIGIT combined with anti-PD-L1.
  • dLN and tumors were collected on day 7 post-treatment for phenotypic characterization of CD8 + T cells by flow cytometry.
  • n 4 per group; mean and s.d.
  • FIG.14F is a set of charts showing the frequencies of CD226 + (left) or CD226- (right) p15E + CD8 + Teff/Tem cells co-expressing Tox in dLN (left) or tumor (right) as a percentage of CD45 + cells in mice with established EO771 tumors that were treated with an isotype control Ab or anti-TIGIT combined with anti- PD-L1.
  • dLN and tumors were collected on day 7 post-treatment for phenotypic characterization of CD8 + T cells by flow cytometry.
  • n 4 per group; mean and s.d. are shown as bar and whiskers; data are representative of one of two independent experiments. p-values are indicated where differences were determined by unpaired t-test to be statistically significant.
  • FIG.15A is an image showing scRNA-seq of 144,413 human CD8 + T cells from blood of patients in a Ph1b NSCLC study of tiragolumab plus atezolizumab (T+A) in which human genes were renamed to their mouse ortholog (if present) and gene expression was normalized before sample integration and projection onto a mouse CD8 + T cell reference UMAP.
  • FIG.15B is a set of plots showing predicted cell type scores for mapped human CD8 + T cells for each assigned mouse CD8 + T cell reference cluster.
  • FIG.15C is a set of box-and-whisker plots showing frequencies of the indicated human predicted clusters in patients with complete response or partial response (CRPR) compared to stable disease or progressive disease (SDPD) on cycle 2 day 1 of treatment with T+A in the Ph1b study. Percent total was calculated as the percentage of the cluster in total CD8 + T cells for each patient.
  • FIG.15D is a forest plot showing the association between high or low expression of the top corresponding human 18-20 signature genes (signature gene score) from each mouse CD8 + T cell cluster or CD8A and overall survival (OS) hazard ratio (HR) T+A or placebo plus atezolizumab (P+A) treatment groups in the Ph2 CITYSCAPE study.
  • CRPR complete response or partial response
  • SDPD stable disease or progressive disease
  • FIG.15E is a set of Kaplan-Meier curves showing OS probability in P+A or T+A treatment groups dichotomized on the basis of high or low CD8 + T cell cluster gene scores from each reference cluster. p- value is from a log-rank test with the null hypothesis that there is no difference between the groups.
  • FIG.15F is a set of Kaplan-Meier curves comparing progression-free survival (PFS, left) or OS (right) in patients from the phase 3 NSCLC OAK study who received atezolizumab monotherapy.
  • FIG.16 is a diagram showing a model of anti-TIGIT plus anti-PD-L1 combination effects on tumor-specific CD8 + T cell differentiation in the syngeneic mouse CT26 tumor model.
  • Combination treatment drives dual expansion of tumor-specific gp70 + CD8 + T cell clones in both dLN and tumor, and egress from dLN and trafficking to tumor is required initially until the tumor is sufficiently seeded by infiltrating cells.
  • Dual expanded gp70 + CD8 + T cell clones highly express CD226 and Ccl5 and have properties of stem cell-like memory / precursor exhausted (Tscm/Tpex) cells such as TCF-1 expression and reduced exhaustion programming as marked by reduction in Tox expression, thereby increasing the pool of CD8 + T cells with antitumor effector activity at the expense of exhaustion.
  • Anti-TIGIT alone phenocopies gp70 + CD8 + T cells responding to combination treatment but does not drive robust dual PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO expansion.
  • Anti-PD-L1 alone does not promote dual expansion nor does it confer protection from the exhaustion pathway.
  • FIG.17 is a set of Kaplan-Meier curves showing progression-free survival (PFS, left) or OS (right) in the PD-L1-positive subset (TPS ⁇ 1%) of patients from the IMpower110 study who received atezolizumab monotherapy. Patients were dichotomized by median gene score calculated using the average expression of the CD8 gene panel comprised of CCR7, CXCR3, CXCR6 and CCL5. DETAILED DESCRIPTION I.
  • “Expression” generally refers to the process by which information (e.g., gene-encoded and/or epigenetic) is converted into the structures present and operating in the cell.
  • Fragments of the transcribed polynucleotide, the translated polypeptide, or polynucleotide and/or polypeptide modifications shall also be regarded as expressed whether they originate from a transcript generated by alternative splicing or a degraded transcript, or from a post-translational processing of the polypeptide, e.g., by proteolysis.
  • “Expressed genes” include those that are transcribed into a polynucleotide as mRNA and then translated into a polypeptide, and also those that are transcribed into RNA but not translated into a polypeptide (for example, transfer and ribosomal RNAs).
  • detecting and “detection” are used herein in the broadest sense to include both qualitative and quantitative measurements of a target molecule. Detecting includes identifying the mere presence of the target molecule in a sample as well as determining whether the target molecule is present in the sample at detectable levels. Detecting may be direct or indirect.
  • the presence and/or expression level/amount of various biomarkers described herein in a sample can be analyzed by a number of methodologies, many of which are known in the art and understood by the skilled artisan, including, but not limited to, immunohistochemistry (“IHC”), Western blot analysis, immunoprecipitation, molecular binding assays, ELISA, ELIFA, fluorescence activated cell sorting (“FACS”), MassARRAY, proteomics, quantitative blood based assays (e.g., Serum ELISA), biochemical enzymatic activity assays, in situ hybridization, fluorescence in situ hybridization (FISH), Southern analysis, Northern analysis, whole genome sequencing, massively parallel DNA sequencing (e.g., next-generation sequencing), NANOSTRING®, polymerase chain reaction (PCR) including quantitative real time PCR (qRT-PCR) and other amplification type detection methods, such as, for example, branched DNA, SISBA, TMA and the like, RNA-seq, microarray analysis,
  • C-C motif chemokine 5 or “CCL5,” as used herein, broadly refers to any native CCL5 from any mammalian source, including primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated.
  • the term encompasses full-length CCL5 and isolated regions or domains of CCL5, e.g., the CCL5 ECD.
  • the term also encompasses naturally occurring variants of CCL5, e.g., splice variants or allelic variants.
  • the amino acid sequence of an exemplary human CCL5 is shown under UniProt Accession No. P13501. Minor sequence variations, especially conservative amino acid substitutions of CCL5 that do not affect CCL5 function and/or activity, are also contemplated by the invention.
  • C-X-C chemokine receptor type 3 or “CXCR3,” as used herein, broadly refers to any native CXCR3 from any mammalian source, including primates (e.g., humans) and rodents (e.g., mice PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO and rats), unless otherwise indicated.
  • the term encompasses full-length CXCR3 and isolated regions or domains of CXCR3, e.g., the CXCR3 ECD.
  • the term also encompasses naturally occurring variants of CXCR3, e.g., splice variants or allelic variants.
  • CXCR3 The amino acid sequence of an exemplary human CXCR3 is shown under UniProt Accession No. P49682. Minor sequence variations, especially conservative amino acid substitutions of CXCR3 that do not affect CXCR3 function and/or activity, are also contemplated by the invention.
  • C-X-C chemokine receptor type 6 or “CXCR6,” as used herein, broadly refers to any native CXCR6 from any mammalian source, including primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated. The term encompasses full-length CXCR6 and isolated regions or domains of CXCR6, e.g., the CXCR6 ECD.
  • CXCR6 also encompasses naturally occurring variants of CXCR6, e.g., splice variants or allelic variants.
  • the amino acid sequence of an exemplary human CXCR6 is shown under UniProt Accession No. O00574. Minor sequence variations, especially conservative amino acid substitutions of CXCR6 that do not affect CXCR6 function and/or activity, are also contemplated by the invention.
  • C-C chemokine receptor type 7 or CCR7 broadly refers to any native CCR7 from any mammalian source, including primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated.
  • the term encompasses full-length CCR7 and isolated regions or domains of CCR7, e.g., the CCR7 ECD.
  • the term also encompasses naturally occurring variants of CCR7, e.g., splice variants or allelic variants.
  • the amino acid sequence of an exemplary human CCR7 is shown under UniProt Accession No. P32248. Minor sequence variations, especially conservative amino acid substitutions of CCR7 that do not affect CCR7 function and/or activity, are also contemplated by the invention.
  • TIGIT or “T-cell immunoreceptor with Ig and ITIM domains” as used herein refers to any native TIGIT from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated.
  • TIGIT is also known in the art as DKFZp667A205, FLJ39873, V-set and immunoglobulin domain-containing protein 9, V-set and transmembrane domain-containing protein 3, VSIG9, VSTM3, and WUCAM.
  • the term encompasses “full-length,” unprocessed TIGIT (e.g., full-length human TIGIT having the amino acid sequence of SEQ ID NO: 1), as well as any form of TIGIT that results from processing in the cell (e.g., processed human TIGIT without a signal sequence, having the amino acid sequence of SEQ ID NO: 2).
  • the term also encompasses naturally occurring variants of TIGIT, e.g., splice variants or allelic variants.
  • the amino acid sequence of an exemplary human TIGIT may be found under UniProt Accession Number Q495A1.
  • PD-L1 or “Programmed Cell Death Ligand 1” refers herein to any native PD-L1 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated.
  • PD-L1 is also known in the art as CD274 molecule, CD274 antigen, B7 homolog 1, PDCD1 Ligand 1, PDCD1LG1, PDCD1L1, B7H1, PDL1, programmed death ligand 1, B7-H1, and B7-H.
  • the term also encompasses naturally occurring variants of PD-L1, e.g., splice variants, or allelic variants.
  • exemplary human PD-L1 may be found under UniProt Accession Number Q9NZQ7 (SEQ ID NO: 3).
  • atezolizumab refers to anti-PD-L1 antagonist antibody having the PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO International Nonproprietary Names for Pharmaceutical Substances (INN) List 112 (WHO Drug Information, Vol.28, No.4, 2014, p.488), or the CAS Registry Number 1380723-44-3.
  • “tiragolumab” is a fully human IgG1/kappa MAb that binds TIGIT and comprises the heavy chain sequence of SEQ ID NO: 4 and the light chain sequence of SEQ ID NO: 5.
  • Tiragolumab comprises two N-linked glycosylation sites (N306) in the Fc domain. Tiragolumab is also described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 117, Vol.31, No.2, published June 9, 2017 (see page 343).
  • Tiragolumab (Genentech) is also known as MTIG7192A, RG6058, or RO7092284. Tiragolumab is described in PCT Pub. Nos.
  • WO2003072305A8 WO2004024068A3, WO2004024072A3, WO2009126688A2, WO2015009856A2, WO2016011264A1, WO2016109546A2, WO2017053748A2, and WO2019165434A1; US Pub. Nos. 2017/0044256, 2017/0037127, 2017/0145093, 2017/260594, 2017/0088613, 2018/0186875, 2019/0119376; and US Pat. Nos. US9873740B2, US10626174B2, US10611836B2, US9499596B2, US8431350B2, US10047158B2, and US10017572B2.
  • administering is meant a method of giving a dosage of a compound (e.g., tiragolumab and/or atezolizumab) or a composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition including an tiragolumab and/or atezolizumab) to a subject.
  • a compound e.g., tiragolumab and/or atezolizumab
  • a composition e.g., a pharmaceutical composition, e.g., a pharmaceutical composition including an tiragolumab and/or atezolizumab
  • the compounds and/or compositions utilized in the methods described herein can be administered, for example, intravenously (e.g., by intravenous infusion), subcutaneously, intramuscularly, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subconjunctivally, intravesicularlly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, in cremes, or in lipid compositions.
  • intravenously e.g., by intravenous infusion
  • subcutaneously intramuscularly, intradermally
  • systemic treatment refers to a treatment that travels through the bloodstream and is capable of contacting multiple organ systems upon a single administration.
  • systemic treatment is well understood by those skilled in the art and is equivalent to systemic therapy.
  • a “fixed” or “flat” dose of a therapeutic agent e.g., tiragolumab or atezolizumab
  • BSA body surface area
  • the fixed or flat dose is therefore not provided as a mg/kg dose or a mg/m 2 dose, but rather as an absolute amount of the therapeutic agent (e.g., mg).
  • treatment or “treating” refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include delaying or decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis.
  • an individual is successfully “treated” if one or more symptoms associated with cancer are mitigated or eliminated, including, but are not limited to, reducing the proliferation of (or destroying) cancerous cells, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and/or prolonging survival of individuals.
  • “in conjunction with” refers to administration of one treatment modality in addition to another treatment modality. As such, “in conjunction with” refers to administration of one treatment modality before, during, or after administration of the other treatment modality to the individual.
  • a “disorder” or “disease” is any condition that would benefit from treatment including, but not limited to, disorders that are associated with some degree of abnormal cell proliferation, e.g., cancer, e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC).
  • cancer e.g., lung cancer, e.g., non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • lung cancer such as non-small cell lung cancer (NSCLC), which includes squamous NSCLC or non-squamous NSCLC, including locally advanced unresectable NSCLC (e.g., Stage IIIB NSCLC), or recurrent or metastatic NSCLC (e.g., Stage IV NSCLC).
  • NSCLC non-small cell lung cancer
  • TSCLC locally advanced unresectable NSCLC
  • recurrent or metastatic NSCLC e.g., Stage IV NSCLC
  • tumor refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues.
  • cancer cancer
  • cancer cancer
  • cancer such as non-small cell lung cancer (NSCLC)
  • NSCLC non-small cell lung cancer
  • squamous NSCLC or non-squamous NSCLC including locally advanced unresectable NSCLC (e.g., Stage IIIB NSCLC), or recurrent or metastatic NSCLC (
  • Metastasis is meant the spread of cancer from its primary site to other places in the body. Cancer cells can break away from a primary tumor, penetrate into lymphatic and blood vessels, circulate through the bloodstream, and grow in a distant focus (metastasize) in normal tissues elsewhere in the body. Metastasis can be local or distant. Metastasis is a sequential process, contingent on tumor cells breaking off from the primary tumor, traveling through the bloodstream, and stopping at a distant site. At the new site, the cells establish a blood supply and can grow to form a life-threatening mass. Both stimulatory and inhibitory molecular pathways within the tumor cell regulate this behavior, and interactions between the tumor cell and host cells in the distant site are also significant.
  • an “effective amount” of a compound for example, tiragolumab or atezolizumab, or a composition (e.g., pharmaceutical composition) thereof, is at least the minimum amount required to achieve the desired therapeutic result, such as a measurable increase in overall survival or progression- free survival of a particular disease or disorder (e.g., cancer, e.g., lung cancer (e.g., NSCLC)).
  • An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the subject.
  • An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects.
  • beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes presenting during development of the disease.
  • beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease (e.g., reduction or delay in cancer-related pain, symptomatic skeletal-related events (SSE), reduction in symptoms per the European Organization for Research and Treatment of Cancer Quality-of-Life PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO Questionnaire (EORTC QLQ-C30, e.g., fatigue, nausea, vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, or general level of physical emotional, cognitive, or social functioning), reduction in pain as measured by, e.g., the 10-point pain severity (measured at its worst) numerical rating scale (NRS), and/or reduction in symptoms associated with lung cancer per the health-related quality of life (HRQoL) questionnaire as assessed by symptoms in lung cancer (SILC) scale (e.g., time to deterioration (TTD) in cough dyspenea and chest pain), increasing the quality of symptoms
  • progression-free survival or radiographic progression-free survival rPFS
  • delay of unequivocal clinical progression e.g., cancer-related pain progression, symptomatic skeletal-related event, deterioration in Eastern Cooperative Group Oncology Group (ECOG) Performance Status (PS) (e.g., how the disease affects the daily living abilities of the patient), and/or initiation of next systemic anti-cancer therapy), and/or delaying time to lung-specific antigen progression), and/or prolonging survival.
  • ECOG Eastern Cooperative Group Oncology Group
  • PS Performance Status
  • an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e., slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and/or relieving to some extent one or more of the symptoms associated with the disorder.
  • An effective amount can be administered in one or more administrations.
  • an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly.
  • an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.
  • an “effective amount” may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.
  • “Individual response” or “response” can be assessed using any endpoint indicating a benefit to the subject, including, without limitation, (1) inhibition, to some extent, of disease progression (e.g., progression of cancer, e.g., lung cancer (e.g., NSCLC)), including slowing down and complete arrest; (2) a reduction in tumor size; (3) inhibition (i.e., reduction, slowing down or complete stopping) of cancer cell infiltration into adjacent peripheral organs and/or tissues; (4) inhibition (i.e., reduction, slowing down or complete stopping) of metastasis; (5) relief, to some extent, of one or more symptoms associated with the disease or disorder (e.g., cancer, e.g., lung cancer (e.g., NSCLC)); (6) increase or extension in the length of survival, including overall survival and progression-free survival; and/or (9) decreased mortality at a given point of time following treatment.
  • disease progression e.g., progression of cancer, e.g., lung cancer (
  • CR complete response
  • PR partial response
  • ORR objective response rate
  • an “effective response” of a subject or a subject’s “responsiveness” to treatment with a medicament and similar wording refers to the clinical or therapeutic benefit imparted to a subject as risk for, or suffering from, a disease or disorder, such as cancer.
  • a disease or disorder such as cancer.
  • such benefit includes any one or more of: extending survival (including overall survival and progression free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer.
  • a subject who “does not have an effective response” to treatment refers to a subject who does not have any one of extending survival (including overall survival and progression free survival); resulting in an objective response (including a complete response or a partial response); or improving signs or symptoms of cancer.
  • survival refers to the patient remaining alive, and includes overall survival as well as progression-free survival.
  • overall survival refers to the percentage of subjects in a group who are alive after a particular duration of time, e.g., 1 year or 5 years from the time of diagnosis or treatment.
  • progression-free survival refers to the length of time during and after treatment during which the disease being treated (e.g., cancer, e.g., lung cancer (e.g., NSCLC)) does not get worse. Progression-free survival may include the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease.
  • stable disease or “SD” refers to neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest SLD since the treatment started.
  • progressive disease or “PD” refers to at least a 20% increase in the SLD of target lesions, taking as reference the smallest SLD recorded since the treatment started or the presence of one or more new lesions.
  • delaying progression of a disorder or disease means to defer, hinder, slow, retard, stabilize, and/or postpone development of the disease or disorder (e.g., cancer, e.g., lung cancer (e.g., NSCLC)). This delay can be of varying lengths of time, depending on the history of the disease and/or subject being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the subject does not develop the disease.
  • CNS central nervous system
  • extending survival is meant increasing overall or progression free survival in a treated patient relative to an untreated patient (e.g., relative to a patient not treated with the medicament), or relative to a patient who does not express a biomarker at the designated level, and/or relative to a patient treated with an approved anti-tumor agent.
  • An objective response refers to a measurable response, including complete response (CR) or partial response (PR).
  • CR complete response
  • PR partial response
  • hazard ratio or “HR” is a statistical definition for rates of events.
  • hazard ratio is defined as representing the probability of an event (e.g., PFS or OS) in the experimental (e.g., treatment) group/arm divided by the probability of an event in the control group/arm at any specific point in time.
  • An HR with a value of 1 indicates that the relative risk of an PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO endpoint (e.g., death) is equal in both the “treatment” and “control” groups; a value greater than 1 indicates that the risk is greater in the treatment group relative to the control group; and a value less than 1 indicates that the risk is greater in the control group relative to the treatment group.
  • “Hazard ratio” in progression-free survival analysis is a summary of the difference between two progression- free survival curves, representing the reduction in the risk of death on treatment compared to control, over a period of follow-up.
  • “Hazard ratio” in overall survival analysis is a summary of the difference between two overall survival curves, representing the reduction in the risk of death on treatment compared to control, over a period of follow-up.
  • the “Ventana SP263 IHC assay” (also referred to herein as the Ventana SP263 CDx assay) is conducted according to the Ventana PD-L1 (SP263) Assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.
  • the “Ventana SP142 IHC assay” is conducted according to the Ventana PD-L1 (SP142) Assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.
  • tumor-infiltrating immune cell refers to any immune cell present in a tumor or a sample thereof. Tumor-infiltrating immune cells include, but are not limited to, intratumoral immune cells, peritumoral immune cells, other tumor stroma cells (e.g., fibroblasts), or any combination thereof.
  • Such tumor-infiltrating immune cells can be, for example, T lymphocytes (such as CD8+ T lymphocytes and/or CD4+ T lymphocytes), B lymphocytes, or other bone marrow-lineage cells, including granulocytes (e.g., neutrophils, eosinophils, and basophils), monocytes, macrophages, dendritic cells (e.g., interdigitating dendritic cells), histiocytes, and natural killer cells.
  • Biomarkers include, but are not limited to, polypeptides, polynucleotides (e.g., DNA, and/or RNA), polynucleotide copy number alterations (e.g., DNA copy numbers), polypeptide and polynucleotide modifications (e.g., posttranslational modifications), carbohydrates, and/or glycolipid-based molecular markers.
  • “subject” or “individual” means a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline. In some embodiments, the subject is a human. Patients are also subjects herein.
  • sample refers to a composition that is obtained or derived from a subject and/or individual of interest that contains a cellular and/or other molecular entity that is to be characterized and/or identified, for example based on physical, biochemical, chemical and/or physiological characteristics.
  • tumor sample refers to any sample obtained from a subject of interest that would be expected or is known to contain the cellular and/or molecular entity that is to be characterized.
  • the sample is a tumor tissue sample (e.g., a lung cancer sample (e.g., a NSCLC sample)).
  • samples include, PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO but are not limited to, primary or cultured cells or cell lines, cell supernatants, cell lysates, platelets, serum, plasma, vitreous fluid, lymph fluid, synovial fluid, follicular fluid, seminal fluid, amniotic fluid, milk, whole blood, blood-derived cells, urine, cerebro-spinal fluid, saliva, sputum, tears, perspiration, mucus, stool, tumor lysates, and tissue culture medium, tissue extracts such as homogenized tissue, cellular extracts, and combinations thereof.
  • the sample is a tumor draining lymph node (dLN) sample.
  • dLN tumor draining lymph node
  • tissue sample and “cell sample” mean a collection of similar cells obtained from a tissue of a subject or individual.
  • the source of the tissue or cell sample may be solid tissue as from a fresh, frozen, and/or preserved organ, tissue sample, biopsy, and/or aspirate; blood or any blood constituents such as plasma; bodily fluids such as cerebral spinal fluid, amniotic fluid, peritoneal fluid, or interstitial fluid; cells from any time in gestation or development of the subject.
  • the tissue sample may also be primary or cultured cells or cell lines.
  • the tissue or cell sample is obtained from a diseased tissue/organ.
  • the tissue sample may contain compounds which are not naturally intermixed with the tissue in nature such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like.
  • a “reference sample,” “reference cell,” “reference tissue,” “control sample,” “control cell,” or “control tissue,” as used herein, refers to a sample, cell, tissue, standard, or level that is used for comparison purposes.
  • a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissue or cells) of the same subject.
  • a reference sample is obtained from an untreated tissue and/or cell of the body of the same subject.
  • a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissues or cells) of a subject who is not the subject.
  • a reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from an untreated tissue and/or cell of the body of an individual who is not the subject.
  • protein refers to any native protein from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), unless otherwise indicated.
  • the term encompasses “full-length,” unprocessed protein as well as any form of the protein that results from processing in the cell.
  • the term also encompasses naturally occurring variants of the protein, e.g., splice variants or allelic variants.
  • Polynucleotide or “nucleic acid,” as used interchangeably herein, refers to polymers of nucleotides of any length, and include DNA and RNA.
  • nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase, or by a synthetic reaction.
  • polynucleotides as defined herein include, without limitation, single- and double-stranded DNA, DNA including single- and double-stranded regions, single- and double-stranded RNA, and RNA including single- and double-stranded regions, hybrid molecules comprising DNA and RNA that may be single- stranded or, more typically, double-stranded or include single- and double-stranded regions.
  • polynucleotide refers to triple-stranded regions comprising RNA or DNA or both RNA and DNA.
  • the strands in such regions may be from the same molecule or from different molecules.
  • the regions may include all of one or more of the molecules, but more typically involve only a region of some of the molecules.
  • One of the molecules of a triple-helical region often is an oligonucleotide.
  • polynucleotide and “nucleic acid” specifically includes mRNA and cDNAs.
  • a polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. If present, modification to the nucleotide structure may be imparted before or after assembly of the polymer. The sequence of nucleotides may be interrupted by non-nucleotide components. A polynucleotide may be further modified after synthesis, such as by conjugation with a label.
  • modifications include, for example, “caps,” substitution of one or more of the naturally-occurring nucleotides with an analog, internucleotide modifications such as, for example, those with uncharged linkages (e.g., methyl phosphonates, phosphotriesters, phosphoamidates, carbamates, and the like) and with charged linkages (e.g., phosphorothioates, phosphorodithioates, and the like), those containing pendant moieties, such as, for example, proteins (e.g., nucleases, toxins, antibodies, signal peptides, poly-L-lysine, and the like), those with intercalators (e.g., acridine, psoralen, and the like), those containing chelators (e.g., metals, radioactive metals, boron, oxidative metals, and the like), those containing alkylators, those with modified linkages (e.g., alpha anomeric nucleic acids
  • any of the hydroxyl groups ordinarily present in the sugars may be replaced, for example, by phosphonate groups, phosphate groups, protected by standard protecting groups, or activated to prepare additional linkages to additional nucleotides, or may be conjugated to solid or semi-solid supports.
  • the 5’ and 3’ terminal OH can be phosphorylated or substituted with amines or organic capping group moieties of from 1 to 20 carbon atoms.
  • Other hydroxyls may also be derivatized to standard protecting groups.
  • Polynucleotides can also contain analogous forms of ribose or deoxyribose sugars that are generally known in the art, including, for example, 2’-O- methyl-, 2’-O-allyl-, 2’-fluoro-, or 2’-azido-ribose, carbocyclic sugar analogs, ⁇ -anomeric sugars, epimeric sugars such as arabinose, xyloses or lyxoses, pyranose sugars, furanose sugars, sedoheptuloses, acyclic analogs, and abasic nucleoside analogs such as methyl riboside.
  • One or more phosphodiester linkages may be replaced by alternative linking groups.
  • linking groups include, but are not limited to, embodiments wherein phosphate is replaced by P(O)S (“thioate”), P(S)S (“dithioate”), “(O)NR2 (“amidate”), P(O)R, P(O)OR’, CO or CH2 (“formacetal”), in which each R or R’ is independently H or substituted or unsubstituted alkyl (1-20 C) optionally containing an ether (-O-) linkage, aryl, alkenyl, cycloalkyl, cycloalkenyl or araldyl. Not all linkages in a polynucleotide need be identical.
  • Carriers as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution.
  • physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEENTM, polyethylene glycol (PEG), and PLURONICSTM.
  • buffers such as phosphate, citrate, and other organic acids
  • pharmaceutically acceptable indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.
  • pharmaceutical formulation refers to a preparation which is in such form as to permit the biological activity of an active ingredient contained therein to be effective, and which contains no additional components which are unacceptably toxic to a subject to which the formulation would be administered.
  • the invention provides a method of identifying an individual having a non-small cell lung cancer (NSCLC) who may benefit from a treatment comprising atezolizumab and tiragolumab, the method comprising detecting an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 (e.g., one, two, three, or all four of CCL5, CXCR3, CCR7, and CXCR6) in a sample from the individual, wherein an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 that is at or above a reference expression level of CCL5, CXCR3, CCR7, or CXCR6 (e.g., an expression level of one, two, three, or all four of CCL5, CXCR3, CCR7, and CXCR6 that is at or above a reference expression level of CCL5, CXCR
  • the invention provides a method of identifying an individual having a NSCLC who may benefit from a treatment comprising atezolizumab and tiragolumab, the method comprising detecting an expression level of CCL5 in a sample from the individual, wherein an expression level of CCL5 that is at or above a reference expression level of CCL5 identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the invention provides a method of identifying an individual having a NSCLC who may benefit from a treatment comprising atezolizumab and tiragolumab, the method comprising detecting an expression level of CXCR3 in a sample from the individual, wherein an expression level of CXCR3 that is at or above a reference expression level of CXCR3 identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the invention provides a method of identifying an individual having a NSCLC who may benefit from a treatment comprising atezolizumab and tiragolumab, the method comprising detecting an expression level of CCR7 in a sample from the individual, wherein an expression level of PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO CCR7 that is at or above a reference expression level of CCR7 identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the invention provides a method of identifying an individual having a NSCLC who may benefit from a treatment comprising atezolizumab and tiragolumab, the method comprising detecting an expression level of CXCR6 in a sample from the individual, wherein an expression level of CXCR6 that is at or above a reference expression level of CXCR6 identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the individual has an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in the sample that is at or above a reference expression level of CCL5, CXCR3, CCR7, or CXCR6, and the method further comprises administering to the individual an effective amount of atezolizumab and tiragolumab (e.g., an effective amount of atezolizumab and tiragolumab as described in Section III herein).
  • an effective amount of atezolizumab and tiragolumab e.g., an effective amount of atezolizumab and tiragolumab as described in Section III herein.
  • the invention provides a method of selecting a therapy for an individual having a NSCLC, the method comprising detecting an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 (e.g., one, two, three, or all four of CCL5, CXCR3, CCR7, and CXCR6) in a sample from the individual, wherein an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 that is at or above a reference expression level of CCL5, CXCR3, CCR7, or CXCR6 (e.g., an expression level of one, two, three, or all four of CCL5, CXCR3, CCR7, and CXCR6 that is at or above a reference expression level of CCL5, CXCR3, CCR7, or CXCR6) identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the invention provides a method of selecting a therapy for an individual having a NSCLC who may benefit from a treatment comprising atezolizumab and tiragolumab, the method comprising detecting an expression level of CCL5 in a sample from the individual, wherein an expression level of CCL5 that is at or above a reference expression level of CCL5 identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the invention provides a method of selecting a therapy for an individual having a NSCLC who may benefit from a treatment comprising atezolizumab and tiragolumab, the method comprising detecting an expression level of CXCR3 in a sample from the individual, wherein an expression level of CXCR3 that is at or above a reference expression level of CXCR3 identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the invention provides a method of selecting a therapy for an individual having a NSCLC who may benefit from a treatment comprising atezolizumab and tiragolumab, the method comprising detecting an expression level of CCR7 in a sample from the individual, wherein an expression level of CCR7 that is at or above a reference expression level of CCR7 identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the invention provides a method of selecting a therapy for an individual having a NSCLC who may benefit from a treatment comprising atezolizumab and tiragolumab, the method comprising detecting an expression level of CXCR6 in a sample from the individual, wherein an PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO expression level of CXCR6 that is at or above a reference expression level of CXCR6 identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the individual has an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in the sample that is at or above a reference expression level of CCL5, CXCR3, CCR7, or CXCR6, and the method further comprises administering to the individual an effective amount of atezolizumab and tiragolumab (e.g., an effective amount of atezolizumab and tiragolumab as described in Section III herein).
  • an effective amount of atezolizumab and tiragolumab e.g., an effective amount of atezolizumab and tiragolumab as described in Section III herein.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising (a) detecting an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 (e.g., one, two, three, or all four of CCL5, CXCR3, CCR7, and CXCR6) in a sample from the individual, wherein the expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 is at or above a reference expression level of CCL5, CXCR3, CCR7, or CXCR6 and thereby identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab; and (b) administering an effective amount of atezolizumab and tiragolumab to the individual.
  • CCL5, CXCR3, CCR7, and CXCR6 e.g., one, two, three, or all four of CCL5, CXCR3, CCR7, and CXCR6
  • the invention provides a method of treating an individual having a NSCLC, the method comprising (a) detecting an expression level of CCL5 in a sample from the individual, wherein the expression level of CCL5 is at or above a reference expression level of CCL5 and thereby identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab; and (b) administering an effective amount of atezolizumab and tiragolumab to the individual.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising (a) detecting an expression level of CXCR3 in a sample from the individual, wherein the expression level of CXCR3 is at or above a reference expression level of CXCR3 and thereby identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab; and (b) administering an effective amount of atezolizumab and tiragolumab to the individual.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising (a) detecting an expression level of CCR7 in a sample from the individual, wherein the expression level of CCR7 is at or above a reference expression level of CCR7 and thereby identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab; and (b) administering an effective amount of atezolizumab and tiragolumab to the individual.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising (a) detecting an expression level of CXCR6 in a sample from the individual, wherein the expression level of CXCR6 is at or above a reference expression level of CXCR6 and thereby identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab; and (b) administering an effective amount of atezolizumab and tiragolumab to the individual.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising administering atezolizumab and tiragolumab to the individual, wherein the individual has been determined to have an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 (e.g., an expression level of one, two, three, or all four of CCL5, CXCR3, CCR7, and CXCR6) that is at or PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO above a reference expression level of CCL5, CXCR3, CCR7, or CXCR6, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • CCL5 e.g., an expression level of one, two, three, or all four of CCL5, CXCR3, CCR7, and CXCR6
  • the invention provides a method of treating an individual having a NSCLC, the method comprising administering atezolizumab and tiragolumab to the individual, wherein the individual has been determined to have an expression level of CCL5 that is at or above a reference expression level of CCL5, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising administering atezolizumab and tiragolumab to the individual, wherein the individual has been determined to have an expression level of CXCR3 that is at or above a reference expression level of CXCR3, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising administering atezolizumab and tiragolumab to the individual, wherein the individual has been determined to have an expression level of CCR7 that is at or above a reference expression level of CCR7, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising administering atezolizumab and tiragolumab to the individual, wherein the individual has been determined to have an expression level of CXCR6 that is at or above a reference expression level of CXCR6, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the invention provides use of atezolizumab and/or tiragolumab in the manufacture of a medicament for the treatment of an individual having a NSCLC, wherein the individual has been determined to have an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in a sample from the individual that is at or above a reference expression level of CCL5, CXCR3, CCR7, or CXCR6, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the invention provides atezolizumab and/or tiragolumab for use in treating an individual having a NSCLC, wherein the individual has been determined to have an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 in a sample from the individual that is at or above a reference expression level of CCL5, CXCR3, CCR7, or CXCR6, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • An individual who benefits from receiving treatment with atezolizumab and tiragolumab may experience, for example, a delay or prevention in the occurrence or recurrence of NSCLC, alleviation of symptoms of the cancer, diminishment of any direct or indirect pathological consequences of the cancer, prevention of metastasis, decrease in the rate of disease progression, amelioration or palliation of the disease state, or remission or improved prognosis.
  • the benefit achieved by the treatment comprising atezolizumab and tiragolumab is a clinical response, e.g., a complete response (CR) or a partial response (PR) (e.g., an individual treated by the method has an increased likelihood of achieving a CR or PR and/or the frequency of CR or PR is increased in the population of individuals treated according to the method).
  • a clinical response e.g., a complete response (CR) or a partial response (PR)
  • CR complete response
  • PR partial response
  • an individual treated by the method has an increased likelihood of achieving a CR or PR and/or the frequency of CR or PR is increased in the population of individuals treated according to the method.
  • the individual has an expression level of one or more of CCL5, CXCR3, and CCR7 (e.g., an expression level of one, two, or all three of CCL5, CXCR3, and CCR7) in the sample that is at or above a reference expression level of CCL5, CXCR3, or CCR7 and the benefit is an increase in overall survival (OS) hazard ratio (HR) (e.g., an increase in the average OS HR of a population of individuals treated according to the method).
  • OS overall survival
  • HR hazard ratio
  • the individual has an expression level of one or more of CCL5, CXCR3, and CXCR6 (e.g., an expression level of one, two, or all three of CCL5, CXCR3, and CXCR6) in the sample that is at or above a reference expression level of CCL5, CXCR3, or CXCR6 and the benefit is an increase in overall survival (OS) (e.g., an increase in the duration of OS experienced by an individual treated according to the method or an increase in the average OS of a population of individuals treated according to the method).
  • OS overall survival
  • An increased clinical response likelihood, OS HR, and/or OS may be determined by comparison to, e.g., an untreated reference individual and/or a reference population of individuals; a reference individual and/or a reference population of individuals who have received a control treatment, such as one or more previously approved treatments or marketed products for treatment of the cancer; and/or a reference individual and/or a reference population of individuals who have been treated with atezolizumab or tiragolumab as a monotherapy.
  • the increased clinical response likelihood, OS HR, and/or OS is determined relative to a reference individual and/or a reference population of individuals having cancer that have been treated with a treatment comprising atezolizumab and tiragolumab, wherein the reference individual and/or each individual in the reference population has an expression level of each of CCL5, CXCR3, CCR7, and CXCR6 that is below a respective reference expression level.
  • Reference expression levels are described herein and may be, for example, a median expression level of CCL5, CXCR3, CCR7, or CXCR6 in a reference population of individuals having a NSCLC. The skilled person is readily able to decide whether a given clinical outcome is improved in accordance with the invention.
  • “improved” in this context means that the clinical outcome resulting from the treatment of an individual having an expression level of one or more of CCL5, CXCR3, CCR7, and CXCR6 that is above a respective reference expression level with a treatment comprising atezolizumab and tiragolumab is at least 3% higher, at least 5% higher, at least 7% higher, at least 10% higher, at least 15% higher, at least 20% higher, at least 25% higher, at least 30% higher, at least 40% PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO higher, at least 50% higher, at least 75% higher, at least 100% higher, or at least 120% higher, as compared to the clinical outcome resulting from a comparator treatment as described above.
  • the duration of OS experienced by an individual treated according to the method or the average OS of a population of individuals treated according to the method is increased by at least 3%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 100%, or at least 120%.
  • the time at which the clinical outcome/clinical endpoint is assessed can readily be determined by the skilled person. In principle, it is determined at a timepoint when the difference in the clinical outcome/clinical endpoint between the two treatments becomes evident.
  • This time may, for example, be at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, or at least 48 months after the beginning of the treatment.
  • the invention provides a method of identifying an individual having a NSCLC who may benefit from a treatment comprising atezolizumab and tiragolumab, the method comprising detecting an expression level of each of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score that is at or above a reference gene signature score identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the individual has a gene signature score in the sample that is at or above a reference gene signature score, and the method further comprises administering to the individual an effective amount of atezolizumab and tiragolumab (e.g., an effective amount of atezolizumab and tiragolumab as described in Section III herein).
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, and CXCR6 in the sample from the individual.
  • the method comprises further detecting the expression level of CCR7 in the sample from the individual, and the gene signature score is an average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.
  • the invention provides a method of identifying an individual having a NSCLC who may benefit from a treatment comprising atezolizumab and tiragolumab, the method comprising detecting an expression level of each of CCL5, CXCR3, CXCR6, and CCR7 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score that is at or above a reference gene signature score identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the invention provides a method of identifying an individual having a NSCLC (e.g., a PD-L1-positive NSCLC, e.g., a NSCLC having a PD-L1 tumor proportion score (TPS) ⁇ 1% as determined using the Ventana (SP263) PD-L1 IHC assay) who may benefit from a treatment comprising atezolizumab (e.g., atezolizumab monotherapy), the method comprising detecting an expression level of each of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score that is at or above a reference gene signature score identifies the individual as one who may benefit from a treatment comprising atezolizumab.
  • a NSCLC e.g., a PD-L1-positive NSCLC, e.g., a NSCLC having a PD-L1 tumor proportion score (TPS) ⁇ 1%
  • the individual has a gene signature score in the sample that is at or above a reference gene signature score, and the method further comprises administering to the individual an effective amount of atezolizumab (e.g., an effective amount of atezolizumab as described in Section III herein).
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, and CXCR6 in the sample from the individual.
  • the method comprises further detecting the expression level of CCR7 in the sample from the individual, and the gene signature score is an average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.
  • the invention provides a method of identifying an individual having a NSCLC who may benefit from a treatment comprising atezolizumab (e.g., atezolizumab monotherapy), the method comprising detecting an expression level of each of CCL5, CXCR3, CXCR6, and CCR7 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score that is at or above a reference gene signature score identifies the individual as one who may benefit from a treatment comprising atezolizumab.
  • the individual has not previously been treated for NSCLC (e.g., has not previously been treated for Stage IV NSCLC).
  • the invention provides a method for selecting a therapy for an individual having a NSCLC, the method comprising detecting an expression level of each of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score that is at or above a reference gene signature score identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the individual has a gene signature score in the sample that is at or above a reference gene signature score, and the method further comprises administering to the individual an effective amount of atezolizumab and tiragolumab (e.g., an effective amount of atezolizumab and tiragolumab as described in Section III herein).
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, and CXCR6 in the sample from the individual.
  • the method comprises further detecting the expression level of CCR7 in the sample from the individual, and the gene signature score is an average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.
  • the invention provides a method of selecting a therapy for an individual having a NSCLC, the method comprising detecting an expression level of each of CCL5, CXCR3, CXCR6, and CCR7 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score that is at or above a reference gene signature score identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab.
  • the invention provides a method for selecting a therapy for an individual having a NSCLC (e.g., a PD-L1-positive NSCLC, e.g., a NSCLC having a PD-L1 tumor proportion score (TPS) ⁇ 1% as determined using the Ventana (SP263) PD-L1 IHC assay), the method comprising detecting an expression level of each of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score that is at or above a reference gene signature score identifies the individual as one who may benefit from a treatment comprising atezolizumab (e.g., atezolizumab monotherapy).
  • a NSCLC e.g., a PD-L1-positive NSCLC, e.g., a NSCLC having a PD-L1 tumor proportion score (TPS) ⁇ 1% as determined using the Ventana (SP263) PD
  • the individual has a gene signature score in the sample that is at or above a reference gene signature score, and the method further comprises administering to the individual an effective amount of atezolizumab (e.g., an effective amount of atezolizumab as described in Section III herein).
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, and CXCR6 in the sample from the individual.
  • the method comprises further detecting the expression level of CCR7 in the sample from the individual, and the gene signature score is an average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.
  • the invention provides a method of selecting a therapy for an individual having a NSCLC, the method comprising detecting an expression level of each of CCL5, CXCR3, CXCR6, and CCR7 in a sample from the individual and determining a gene signature score therefrom, wherein a gene signature score that is at or above a reference gene signature score identifies the individual as one who may benefit from a treatment comprising atezolizumab (e.g., atezolizumab monotherapy).
  • the individual has not previously been treated for NSCLC (e.g., has not previously been treated for Stage IV NSCLC).
  • the invention provides a method of treating an individual having a NSCLC, the method comprising (a) detecting an expression level of each of CCL5, CXCR3, and CXCR6 in a sample PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO from the individual and determining a gene signature score therefrom, wherein the gene signature score is at or above a reference gene signature score and thereby identifies the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab; and (b) administering an effective amount of atezolizumab and tiragolumab to the individual.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising administering atezolizumab and tiragolumab to the individual, wherein the individual has been determined to have a gene signature score that is at or above a reference gene signature score, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab, and wherein the gene signature score is based on the expression level of each of CCL5, CXCR3, CXCR6, and CCR7 detected in a sample from the individual.
  • the invention provides atezolizumab and/or tiragolumab for use in treating an individual having a NSCLC, wherein the individual has been determined to have a gene signature score that is at or above a reference gene signature score, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab, wherein the gene signature score is based on the expression level of each of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.
  • the invention provides a method of treating an individual having a NSCLC (e.g., a PD-L1-positive NSCLC, e.g., a NSCLC having a PD-L1 tumor proportion score (TPS) ⁇ 1% as determined using the Ventana (SP263) PD-L1 IHC assay), the method comprising (a) detecting an expression level of each of CCL5, CXCR3, and CXCR6 in a sample from the individual and determining a gene signature score therefrom, wherein the gene signature score is at or above a reference gene signature score and thereby identifies the individual as one who may benefit from a treatment comprising atezolizumab (e.g., atezolizumab monotherapy); and (b) administering an effective amount of atezolizumab to the individual.
  • a NSCLC e.g., a PD-L1-positive NSCLC, e.g., a NSCLC having a PD-L1 tumor proportion score
  • the invention provides a method of treating an individual having a NSCLC (e.g., a PD-L1-positive NSCLC), the method comprising administering atezolizumab to the individual, wherein the individual has been determined to have a gene signature score that is at or above a reference gene signature score, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab (e.g., atezolizumab monotherapy), and wherein the gene signature score is based on the expression level of each of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.
  • the gene signature score is an average of the expression levels of CCL5, CXCR3, and CXCR6 in the sample from the individual.
  • the expression level of CCR7 has been detected in the sample from the individual, and the gene signature score is an average of the expression levels of CCL5, CXCR3, CXCR6, and CCR7 in the sample from the individual.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising (a) detecting an expression level of each of CCL5, CXCR3, CXCR6, and CCR7 in a sample from the individual and determining a gene signature score therefrom, wherein the gene signature score is at or above a reference gene signature score and thereby identifies the individual as one who may benefit from a treatment comprising atezolizumab (e.g., atezolizumab monotherapy); and (b) administering an effective amount of atezolizumab to the individual.
  • atezolizumab e.g., atezolizumab monotherapy
  • the invention provides a method of treating an individual having a NSCLC, the method comprising administering atezolizumab to the individual, wherein the individual has been determined to have a gene signature score that is at or above a reference gene signature score, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab (e.g., atezolizumab monotherapy), and wherein the gene signature score is based on the expression level of each of CCL5, CXCR3, CXCR6, and CCR7 detected in a sample from the individual.
  • the individual has not previously been treated for NSCLC (e.g., has not previously been treated for Stage IV NSCLC).
  • the invention provides use of atezolizumab in the manufacture of a medicament for the treatment of an individual having a NSCLC, wherein the individual has been determined to have a gene signature score that is at or above a reference gene signature score, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab, wherein the gene signature score is based on the expression level of each of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.
  • the invention provides atezolizumab for use in treating an individual having a NSCLC, wherein the individual has been determined to have a gene signature score that is at or above a reference gene signature score, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab, wherein the gene signature score is based on the expression level of each of CCL5, CXCR3, and CXCR6 detected in a sample from the individual.
  • the benefit achieved by the treatment comprising atezolizumab and tiragolumab is a clinical response, e.g., a complete response (CR) or a partial response (PR) (e.g., an individual treated by the method has an increased likelihood of achieving a CR or PR and/or the frequency of CR or PR is increased in the population of individuals treated according to the method).
  • the benefit achieved by the treatment comprising atezolizumab and tiragolumab is an increase in overall survival (OS) hazard ratio (HR) (e.g., an increase in the average OS HR of a population of individuals treated according to the method).
  • OS overall survival
  • HR hazard ratio
  • the benefit achieved by the treatment comprising atezolizumab and tiragolumab is an increase in overall survival (OS) (e.g., an increase in the duration of OS experienced by an individual treated according to the method or an increase in the average OS of a population of individuals treated according to the method).
  • OS overall survival
  • An increased clinical response likelihood, OS HR, and/or OS may be determined by comparison to, e.g., an untreated reference individual and/or a reference population of individuals; a reference individual and/or a reference population of individuals who have received a control treatment, such as one or more previously approved treatments or marketed products for treatment of the cancer; and/or a reference individual and/or a reference population of individuals who have been treated with atezolizumab or tiragolumab as a monotherapy.
  • the increased clinical response likelihood, OS HR, and/or OS is determined relative to a reference individual and/or a reference population of individuals having cancer that have been treated with a treatment comprising atezolizumab and tiragolumab, wherein the reference individual and/or each individual in the reference population has a gene signature score is based on the expression level of (a) each of CCL5, CXCR3, and CXCR6 or (b) each of CCL5, CXCR3, CXCR6, and CCR7 that is below a respective reference gene signature score.
  • the skilled person is readily able to decide whether a given clinical outcome is improved in accordance with the invention.
  • “improved” in this context means that the clinical outcome resulting from the treatment of an individual having a gene signature score is based on the expression level of (a) each of CCL5, CXCR3, and CXCR6 or (b) each of CCL5, CXCR3, CXCR6, and CCR7 that is above a respective reference expression level with a treatment comprising atezolizumab and tiragolumab is at least 3% higher, at least 5% higher, at least 7% higher, at least 10% higher, at least 15% higher, at least 20% higher, at least 25% higher, at least 30% higher, at least 40% higher, at least 50% higher, at least 75% higher, at least 100% higher, or at least 120% higher, as compared to the clinical outcome resulting from a comparator treatment as described above.
  • the duration of OS experienced by an individual treated according to the method or the average OS of a population of individuals treated according to the method is PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO increased by at least 3%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 100%, or at least 120%.
  • the time at which the clinical outcome/clinical endpoint is assessed can readily be determined by the skilled person. In principle, it is determined at a timepoint when the difference in the clinical outcome/clinical endpoint between the two treatments becomes evident.
  • This time may, for example, be at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, or at least 48 months after the beginning of the treatment.
  • Benefit of treatment comprising atezolizumab is an increase in overall survival (OS) (e.g., an increase in the duration of OS experienced by an individual treated according to the method or an increase in the average OS of a population of individuals treated according to the method).
  • OS overall survival
  • the benefit achieved by the treatment comprising atezolizumab is an increase in progression-free survival (PFS) (e.g., an increase in the duration of PFS experienced by an individual treated according to the method or an increase in the average PFS of a population of individuals treated according to the method).
  • PFS progression-free survival
  • An increased OS and/or PFS may be determined by comparison to, e.g., an untreated reference individual and/or a reference population of individuals; a reference individual and/or a reference population of individuals who have received a control treatment, such as one or more previously approved treatments or marketed products for treatment of the cancer.
  • the increased OS and/or PFS is determined relative to a reference individual and/or a reference population of individuals having cancer that have been treated with a treatment comprising a PD-1 axis binding antagonist (e.g., atezolizumab), wherein the reference individual and/or each individual in the reference population has a gene signature score is based on the expression level of (a) each of CCL5, CXCR3, and CXCR6 or (b) each of CCL5, CXCR3, CXCR6, and CCR7 that is below a respective reference gene signature score.
  • a PD-1 axis binding antagonist e.g., atezolizumab
  • “improved” in this context means that the clinical outcome resulting from the treatment of an individual having a gene signature score is based on the expression level of (a) each of CCL5, CXCR3, and CXCR6 or (b) each of CCL5, CXCR3, CXCR6, and CCR7 that is above a respective reference expression level with a treatment comprising atezolizumab and tiragolumab is at least 3% higher, at least 5% higher, at least 7% higher, at least 10% higher, at least 15% higher, at least 20% higher, at least 25% higher, at least 30% higher, at least 40% higher, at least 50% higher, at least 75% higher, at least 100% higher, or at least 120% higher, as compared to the clinical outcome resulting from a comparator treatment as described above.
  • the duration of OS experienced by an individual treated according to the method or the average OS of a population of individuals treated according to the method is PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO increased by at least 3%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 100%, or at least 120%.
  • the duration of PFS experienced by an individual treated according to the method or the average PFS of a population of individuals treated according to the method is increased by at least 3%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 100%, or at least 120%.
  • the time at which the clinical outcome/clinical endpoint is assessed can readily be determined by the skilled person. In principle, it is determined at a timepoint when the difference in the clinical outcome/clinical endpoint between the two treatments becomes evident.
  • This time may, for example, be at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, or at least 48 months after the beginning of the treatment.
  • the invention provides a method of identifying an individual having a NSCLC who may benefit from a treatment comprising atezolizumab and tiragolumab, the method comprising: (a) detecting an expression level of at least two of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 of STAT1, LEF1, IR
  • the individual has (i) a Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, or Mitotic gene signature score in the sample that is at or above a reference gene signature score or (ii) a Cytotox.2 or Cytotox.4 gene signature score that is below a reference gene signature score, and the method further PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO comprises administering to the individual an effective amount of atezolizumab and tiragolumab (e.g., an effective amount of atezolizumab and tiragolumab as described in Section III herein).
  • an effective amount of atezolizumab and tiragolumab e.g., an effective amount of atezolizumab and tiragolumab as described in Section III herein.
  • the gene signature score is an average of the expression levels of the members of the gene signature in the sample from the individual.
  • the reference gene signature score is a pre-assigned gene signature score and/or a gene signature score in a reference population (e.g., a population of individuals having the NSCLC).
  • the gene signature score in the reference population is the median Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox.2, or Cytotox.4 gene signature score in the reference population.
  • the invention provides a method for selecting a therapy for an individual having a NSCLC, the method comprising: (a) detecting an expression level of at least two of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X, e.g., each of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2,
  • the individual has (i) a Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, or Mitotic gene signature score in the sample that is at or above a reference gene signature score or (ii) a Cytotox.2 or Cytotox.4 gene signature score that is below a reference gene signature score, and the method further comprises administering to the individual an effective amount of atezolizumab and tiragolumab (e.g., an effective amount of atezolizumab and tiragolumab as described in Section III herein).
  • the gene signature score is an average of the expression levels of the members of the gene signature in the sample from the individual.
  • the reference gene signature score is a pre-assigned gene signature score and/or a gene signature score in a reference population (e.g., a population of individuals having the NSCLC).
  • the gene signature score in the reference population is the median Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox.2, or Cytotox.4 gene signature score in the reference population.
  • the invention provides a method of treating an individual having a NSCLC, the method comprising: (i) (a) detecting an expression level of at least two of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X, e.g., each of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2,
  • the invention provides a method of treating an individual having a NSCLC, the method comprising administering atezolizumab and tiragolumab to the individual, wherein the individual has been determined to have: (a) a Ccr7.2 gene signature score based on an expression level at least two of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or all 18 of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13,
  • the gene signature score is an average of the expression levels of the members of the gene signature in the sample from the individual.
  • the reference gene signature score is a pre-assigned gene signature score and/or a gene signature score in a reference population (e.g., a population of individuals having the NSCLC).
  • the gene signature score in the reference population is the median Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox.2, or Cytotox.4 gene signature score in the reference population.
  • the invention provides use of atezolizumab and/or tiragolumab in the manufacture of a medicament for the treatment of an individual having a NSCLC, wherein the individual has been determined to have: PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO (i) (a) a Ccr7.2 gene signature score that is at or above a reference gene signature score, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab, wherein the gene signature score is based on the expression level of each of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X detected in a sample from the individual; (b) a Ccr7.3 gene signature score that is at or above
  • the invention provides atezolizumab and/or tiragolumab for use in treating an individual having a NSCLC, wherein the individual has been determined to have: (i) (a) a Ccr7.2 gene signature score that is at or above a reference gene signature score, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab, wherein the gene signature score is based on the expression level of each of STAT1, LEF1, IRGM, CCR7, SELL, RPS24, RPS27, GBP2, RPS29, RPS3A, RPS20, KLF2, RPLP1, RPL13, DAPL1, SMC6, RFLNB, and RPS4X detected in a sample from the individual; (b) a Ccr7.3 gene signature score that is at or above a reference gene signature score, thereby identifying the individual as one who may benefit from a treatment comprising atezolizumab and tiragolumab, wherein the gene
  • the individual has a Ccr7.3, Cxcr3, or Ccl5.1 gene signature score in the sample that is at or above a reference gene signature score and the benefit achieved by the treatment comprising atezolizumab and tiragolumab is a clinical response, e.g., a complete response (CR) or a partial response (PR) (e.g., an individual treated by the method has an increased likelihood of achieving a CR or PR and/or the frequency of CR or PR is increased in the population of individuals treated according to the method).
  • a clinical response e.g., a complete response (CR) or a partial response (PR)
  • CR complete response
  • PR partial response
  • an individual treated by the method has an increased likelihood of achieving a CR or PR and/or the frequency of CR or PR is increased in the population of individuals treated according to the method.
  • the individual has (i) a Ccr7.2, Cxcr3, Ifit, or Mitotic gene signature score in the sample that is at or above a reference gene signature score or (ii) a Cytotox.2 or Cytotox.4 gene signature score that is below a reference gene signature score and the benefit achieved by the treatment comprising atezolizumab and tiragolumab is an increase in overall survival (OS) hazard ratio (HR) (e.g., an increase in the average OS HR of a population of individuals treated according to the method).
  • OS overall survival
  • HR hazard ratio
  • the individual has a Ccr7.2, Ccr7.3, or Cxcr3 gene signature score in the sample that is at or above a reference gene signature score and the benefit achieved by the treatment comprising atezolizumab and tiragolumab is an increase in overall survival (OS) (e.g., an increase in the duration of OS experienced by an individual treated according to the method or an increase in the average OS of a population of individuals treated according to the method).
  • OS overall survival
  • An increased clinical response likelihood, OS HR, and/or OS may be determined by comparison to, e.g., an untreated reference individual and/or a reference population of individuals; a reference individual and/or a reference population of individuals who have received a control treatment, such as one or more previously approved treatments or marketed products for treatment of the cancer; and/or a reference individual and/or a reference population of individuals who have been treated with atezolizumab or tiragolumab as a monotherapy.
  • the increased clinical response likelihood, OS HR, and/or OS is determined relative to a reference individual and/or a reference population of individuals having cancer that have been treated with a treatment comprising atezolizumab and tiragolumab, wherein the reference individual and/or each individual in the reference population has (i) a Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, or Mitotic gene signature score that is below a reference gene signature score and/or (ii) a Cytotox.2 or Cytotox.4 gene signature score that is at or above a reference gene signature score.
  • the skilled person is readily able to decide whether a given clinical outcome is improved in accordance with the invention.
  • “improved” in this context means that the clinical outcome resulting from the treatment of an individual having (i) a Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, or Mitotic gene signature score that is at or above a reference gene signature score and/or (ii) a Cytotox.2 or Cytotox.4 gene signature score that is below a reference gene signature score with a treatment comprising atezolizumab and tiragolumab is at least 3% higher, at least 5% higher, at least 7% higher, at least 10% PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO higher, at least 15% higher, at least 20% higher, at least 25% higher, at least 30% higher, at least 40% higher, at least 50% higher, at least 75% higher, at least 100% higher, or at least 120% higher, as compared to the clinical outcome resulting from a comparator treatment as described above.
  • the duration of OS experienced by an individual treated according to the method or the average OS of a population of individuals treated according to the method is increased by at least 3%, at least 5%, at least 7%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 75%, at least 100%, or at least 120%.
  • the time at which the clinical outcome/clinical endpoint is assessed can readily be determined by the skilled person. In principle, it is determined at a timepoint when the difference in the clinical outcome/clinical endpoint between the two treatments becomes evident.
  • This time may, for example, be at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, or at least 48 months after the beginning of the treatment.
  • D. Samples, expression levels, and PD-L1 status Samples An expression level of one or more of CCL5, CXCR3, CCR7, or CXCR6; a member of any one of the Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox.2, and Cytotox.4 gene signatures and/or a gene signature score may be determined from any suitable sample.
  • Exemplary sample types include, without limitation, a tissue sample, a tumor sample, a blood sample (e.g., a whole blood sample), a plasma sample, a serum sample, and combinations thereof. Samples may be fresh, archival, or frozen.
  • the sample is a tissue sample, e.g., a tumor tissue sample.
  • the tumor tissue sample is a biopsy, e.g., a biopsy of the NSCLC.
  • the sample is a tumor draining lymph node (dLN) sample.
  • dLN tumor draining lymph node
  • the sample is obtained from the individual prior to treatment with atezolizumab and tiragolumab, e.g., is obtained immediately prior to the first administration of atezolizumab and/or tiragolumab, or is obtained at least one day, at least one week, or at least one month prior to the first administration of atezolizumab and/or tiragolumab.
  • Expression levels The expression levels of the one or more genes detected in the methods provided herein may be, e.g., nucleic acid expression levels or protein expression levels. In some aspects, the expression levels are nucleic acid expression levels, e.g., mRNA expression levels.
  • Nucleic acid expression levels may be detected using any suitable method known in the art, e.g., may be determined by RNA-seq, reverse transcriptase quantitative PCR (RT-qPCR), quantitative PCR (qPCR), real-time PCR, quantitative real-time PCR (qRT-PCR), multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, in situ hybridization (ISH), or a combination thereof.
  • Other amplification-based methods include, for example, transcript-mediated amplification (TMA), strand displacement amplification (SDA), nucleic acid sequence based amplification (NASBA), and signal amplification methods such as bDNA.
  • nucleic acid expression levels of the genes described herein may be measured by sequencing-based techniques, such as, for example, RNA-seq, serial analysis of gene expression (SAGE), high-throughput sequencing technologies (e.g., massively parallel sequencing), and Sequenom MassARRAY® technology. Nucleic acid expression levels also may be measured by, for example, NanoString nCounter, and high-coverage expression profiling (HiCEP).
  • sequencing-based techniques such as, for example, RNA-seq, serial analysis of gene expression (SAGE), high-throughput sequencing technologies (e.g., massively parallel sequencing), and Sequenom MassARRAY® technology.
  • Nucleic acid expression levels also may be measured by, for example, NanoString nCounter, and high-coverage expression profiling (HiCEP).
  • nucleic acid expression levels of the genes described herein include electrophoresis, Northern and Southern blot analyses, in situ hybridization (e.g., single or multiplex nucleic acid in situ hybridization), RNAse protection assays, and microarrays (e.g., Illumina BEADARRAYTM technology; Beads Array for Detection of Gene Expression (BADGE)).
  • electrophoresis e.g., electrophoresis, Northern and Southern blot analyses, in situ hybridization (e.g., single or multiplex nucleic acid in situ hybridization), RNAse protection assays, and microarrays (e.g., Illumina BEADARRAYTM technology; Beads Array for Detection of Gene Expression (BADGE)).
  • the expression level is a protein expression level, e.g., a protein expression level determined by mass spectrometry, Western blot, ELISA, immunoprecipitation, immunohistochemistry, immunofluorescence, radioimmunoassay, dot blotting, immunodetection methods, surface plasmon resonance, optical spectroscopy, mass spectrometry, or HPLC.
  • a protein expression level e.g., a protein expression level determined by mass spectrometry, Western blot, ELISA, immunoprecipitation, immunohistochemistry, immunofluorescence, radioimmunoassay, dot blotting, immunodetection methods, surface plasmon resonance, optical spectroscopy, mass spectrometry, or HPLC.
  • Normalization of expression levels e.g., the expression levels of one or more genes detected in the methods provided herein are normalized expression levels, e.g., gene signature score is an average of the normalized expression levels of the one or more genes in the sample
  • the normalization method used may depend on the gene expression methodology used (e.g., one or more housekeeping genes may be used for normalization in the context of an RT-qPCR methodology, but a whole genome or substantially whole genome may be used as a normalization baseline in the context of an RNA-seq methodology).
  • the detected expression level of each gene assayed can be normalized for differences in the amount of the gene(s) assayed, variability in the quality of the samples used, and/or variability between assay runs.
  • normalization may be accomplished by detecting expression of certain one or more normalizing gene(s), including reference gene(s) (e.g., a housekeeping gene (e.g., ⁇ -actin)).
  • the nucleic acid expression levels detected using the methods described herein may be normalized to the expression level of one or more reference genes (e.g., one, two, three, four, five, six, seven, eight, nine, or more reference genes, e.g., a housekeeping gene (e.g., ⁇ -actin)).
  • reference genes e.g., one, two, three, four, five, six, seven, eight, nine, or more reference genes, e.g., a housekeeping gene (e.g., ⁇ -actin)
  • normalization can be based on the average signal or median signal of all of the assayed genes.
  • a measured normalized amount of an mRNA can be compared to the amount found in a reference expression level.
  • the presence and/or expression level/amount measured PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO in a particular subject sample to be analyzed will fall at some percentile within this range, which can be determined by methods well known in the art.
  • the detected expression level of each assayed gene is not normalized. Any statistical approaches known in the art may be used to determine the expression level of each gene.
  • the expression level may reflect the median expression level, median normalized expression level, or mean expression level, or mean normalized expression level.
  • reference expression levels and gene signature scores refer to an expression level or a gene signature score against which another expression level or gene signature score is compared, e.g., to make a diagnostic, predictive, prognostic, and/or therapeutic determination.
  • the reference expression level or reference gene signature score is a pre- assigned reference expression level or reference gene signature score.
  • the reference expression level or reference gene signature score is an expression level or a gene signature score in a reference population (e.g., a population of individuals having the NSCLC).
  • the expression level or gene signature score in the reference population is a median expression level or gene signature score of the reference population.
  • the expression level or gene signature score in the reference population is a mean expression level or gene signature score of the reference population.
  • the expression level or gene signature score is defined as the 25 th percentile, the 26 th percentile, the 27 th percentile, the 28 th percentile, the 29 th percentile, the 30 th percentile, the 31 st percentile, the 32 nd percentile, the 33 rd percentile, the 34 th percentile, the 35 th percentile, the 36 th percentile, the 37 th percentile, the 38 th percentile, the 39 th percentile, the 40 th percentile, the 41 st percentile, the 42 nd percentile, the 43 rd percentile, the 44 th percentile, the 45 th percentile, the 46 th percentile, the 47 th percentile, the 48 th percentile, the 49 th percentile, the 50 th percentile, the 51 st percentile, the 52 nd percentile, the 53 rd percentile, the
  • the reference expression level or reference gene signature score is a cut-off value that significantly separates a first and a second subset of individuals who have been treated with atezolizumab and tiragolumab in the same reference population based on a significant difference PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO between an individual’s responsiveness to treatment with atezolizumab and tiragolumab above the cut-off value or at or below the cut-off value.
  • the individual’s responsiveness to treatment with atezolizumab and tiragolumab is significantly improved relative to the individual’s responsiveness to treatment with atezolizumab and tiragolumab at or above the cut-off value.
  • the reference expression level or reference gene signature score is a cut-off value that significantly separates a first and a second subset of individuals who have been treated with atezolizumab (e.g., atezolizumab monotherapy) in the same reference population based on a significant difference between an individual’s responsiveness to treatment with atezolizumab above the cut-off value or at or below the cut-off value.
  • the individual’s responsiveness to treatment with atezolizumab is significantly improved relative to the individual’s responsiveness to treatment with atezolizumab at or above the cut-off value.
  • PD-L1 status In some aspects, the expression level of PD-L1 has been assessed in the sample from a subject described herein. In some aspects, the sample has been determined to have a PD-L1-positive tumor cell fraction (e.g., by an immunohistochemical (IHC) assay, e.g., by positive staining with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8). Exemplary methods for assessing the expression level of PD-L1 are provided in Section II(F).
  • IHC immunohistochemical
  • TIGIT expression may be determined in terms of the percentage of a tumor sample comprised by tumor-infiltrating immune cells expressing a detectable expression level of TIGIT, as the percentage of tumor-infiltrating immune cells in a tumor sample expressing a detectable expression level of TIGIT, and/or as the percentage of tumor cells in a tumor sample expressing a detectable expression level of TIGIT. It is to be understood that in any of the preceding examples, the percentage of the tumor sample comprised by tumor-infiltrating immune cells may be in terms of the percentage of tumor area covered by tumor-infiltrating immune cells in a section of the tumor sample obtained from the individual, for example, as assessed by IHC using an anti-TIGIT antibody.
  • any suitable anti-TIGIT antibody may be used.
  • the anti-TIGIT antibody is 10A7 (WO 2009/126688A3; U.S. Patent No: 9,499,596).
  • the anti-TIGIT antibody is the anti-human TIGIT rabbit monoclonal antibody clone SP410 (Roche Tissue Diagnostics, Pleasanton, CA).
  • the anti-TIGIT antibody e.g., SP410
  • the anti-TIGIT antibody is detected using the VENTANA OptiView DAB IHC Detection Kit on the automated VENTANA BenchMark ULTRA platform. PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO F.
  • the expression of PD-L1 is assessed in an individual described herein.
  • the methods provided herein may include determining the expression level of PD-L1 in a biological sample (e.g., a tumor sample) obtained from the individual.
  • the expression level of PD-L1 in a biological sample (e.g., a tumor sample) obtained from the individual has been determined prior to initiation of treatment or after initiation of treatment.
  • PD-L1 expression may be determined using any suitable approach. For example, PD-L1 expression may be determined as described in U.S. Patent Application Publication Nos. US20180030138A1 and US20180037655A1.
  • a suitable tumor sample may be used, e.g., a formalin-fixed and paraffin-embedded (FFPE) tumor sample, an archival tumor sample, a fresh tumor sample, or a frozen tumor sample.
  • FFPE formalin-fixed and paraffin-embedded
  • PD-L1 expression may be determined in terms of the percentage of a tumor sample comprised by tumor-infiltrating immune cells expressing a detectable expression level of PD-L1, as the percentage of tumor-infiltrating immune cells in a tumor sample expressing a detectable expression level of PD-L1, and/or as the percentage of tumor cells in a tumor sample expressing a detectable expression level of PD-L1.
  • the percentage of the tumor sample comprised by tumor-infiltrating immune cells may be in terms of the percentage of tumor area covered by tumor-infiltrating immune cells in a section of the tumor sample obtained from the individual, for example, as assessed by IHC using an anti-PD-L1 antibody (e.g., the SP142 antibody).
  • an anti-PD-L1 antibody e.g., the SP142 antibody
  • Any suitable anti-PD-L1 antibody may be used, including, e.g., SP142 (Ventana), SP263 (Ventana), 22C3 (Dako), 28- 8 (Dako), E1L3N (Cell Signaling Technology), 4059 (ProSci, Inc.), h5H1 (Advanced Cell Diagnostics), and 9A11.
  • the anti-PD-L1 antibody is SP142. In other examples, the anti-PD-L1 antibody is SP263. In some examples, the anti-PD-L1 antibody is 22C3. In some examples, the anti-PD- L1 antibody is 28-8.
  • a tumor sample obtained from the individual has a detectable expression level of PD-L1 in less than 1% of the tumor cells in the tumor sample, in 1% or more of the tumor cells in the tumor sample, in from 1% to less than 5% of the tumor cells in the tumor sample, in 5% or more of the tumor cells in the tumor sample, in from 5% to less than 50% of the tumor cells in the tumor sample, or in 50% or more of the tumor cells in the tumor sample.
  • a tumor sample obtained from the individual has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise less than 1% of the tumor sample, more than 1% of the tumor sample, from 1% to less than 5% of the tumor sample, more than 5% of the tumor sample, from 5% to less than 10% of the tumor sample, or more than 10% of the tumor sample.
  • a tumor sample obtained from the individual has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise 5%-19% of the tumor sample (e.g., TIC 5%- 19%); e.g., has a PD-L1 expression level that is PD-L1 low.
  • a tumor sample obtained from the individual has a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise ⁇ 20% of the tumor sample (e.g., TIC ⁇ 20%); e.g., has a PD-L1 expression level that is PD-L1 high.
  • tumor samples that have been determined to have a TIC of greater than, or equal to, 5% are comparable to a CPS of greater than, or equal to, 1.
  • tumor samples may be scored for PD-L1 positivity in tumor-infiltrating immune cells and/or in tumor cells according to the criteria for diagnostic assessment shown in Table 1 and/or Table 2, respectively.
  • Table 1 Tumor-infiltrating immune cell (IC) IHC diagnostic criteria Table 2.
  • Tumor cell (TC) IHC diagnostic criteria in any of the methods, uses, or compositions for use described herein, the individual has a PD-L1-selected tumor (e.g., a proportion of tumor area occupied by PD-L1 expressing tumor-infiltrating immune cells (ICs) is greater than or equal to 5% in the tumor sample as determined by an IHC with the SP142 antibody).
  • the PD-L1-selected tumor is a tumor that has been determined to have a proportion of tumor area occupied by PD-L1 expressing immune cells (ICs) greater than or equal to 5% by an immunohistochemical (IHC) assay.
  • the IHC assay uses the anti-PD-L1 antibody SP142, SP263, 22C3, or 28-8. In some instances, the IHC assay uses anti-PD-L1 antibody SP142. In some instances, the IHC assay uses anti-PD-L1 antibody SP263. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the IHC assay uses anti-PD-L1 antibody 28-8. In some instances, the IC score has been determined to be greater than, or equal to, 5% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay).
  • SP142 Ventana
  • the IC score has been determined to be 2 or 3 (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IC score has been determined to be greater than, or equal to, 1% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IC score has been determined to be greater than, or equal to, 10% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay).
  • the IC score has been determined to be greater than, or equal to, 1% and less than 50% PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IC score has been determined to be greater than, or equal to, 1% and less than 30% (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable protein expression level of PD-L1.
  • the detectable protein expression level of PD-L1 has been determined by an IHC assay.
  • the IHC assay uses anti-PD-L1 antibody SP142.
  • the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 5% of the tumor sample.
  • the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 1% of the tumor sample.
  • the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 1% and less than 5% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor- infiltrating immune cells that comprise greater than, or equal to, 5% and less than 10% of the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells that comprise greater than, or equal to, 10% of the tumor sample.
  • the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 1% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 1% and less than 5% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 5% and less than 50% of the tumor cells in the tumor sample. In some instances, the tumor sample has been determined to have a detectable expression level of PD-L1 in greater than, or equal to, 50% of the tumor cells in the tumor sample.
  • the individual has a PD-L1-selected tumor (e.g., a PD-L1 “high”-selected tumor (e.g., a PD-L1 tumor proportion score (TPS) greater than or equal to 50% in a tumor sample as determined by an IHC with the SP263 antibody)).
  • a PD-L1-selected tumor e.g., a PD-L1 “high”-selected tumor (e.g., a PD-L1 tumor proportion score (TPS) greater than or equal to 50% in a tumor sample as determined by an IHC with the SP263 antibody).
  • TPS tumor proportion score
  • the PD-L1-selected tumor is a PD-L1 “high”-selected tumor.
  • the PD-L1-selected tumor is a tumor that has been determined to have TPS greater than or equal to 50% by an immunohistochemical (IHC) assay.
  • IHC immunohistochemical
  • the IHC assay uses the anti-PD-L1 antibody SP263, SP142, 22C3, or 28-8. In some instances, the IHC assay uses anti-PD-L1 antibody SP263. In some instances, the IHC assay uses anti-PD-L1 antibody SP142. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the TPS has been determined to be greater than, or equal to, 50% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TPS has been determined to be less than 50% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay).
  • the TPS has been determined to be greater than, or equal to, 1% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TPS has been determined to be greater than, or equal to, 1% and less than 50% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay).
  • PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO In some instances, in any of the methods, uses, or compositions for use described herein, a tumor sample obtained from the individual has a detectable protein expression level of PD-L1.
  • the detectable protein expression level of PD-L1 has been determined by an IHC assay.
  • the IHC assay uses anti-PD-L1 antibody SP263.
  • the tumor sample has been determined to have a PD-L1-positive tumor cell fraction greater than, or equal to, 50% of the tumor sample.
  • the tumor sample has been determined to have a PD-L1-positive tumor cell fraction less than 50% of the tumor sample.
  • the tumor sample has been determined to have a PD-L1-positive tumor cell fraction greater than, or equal to, 1% and less than 50% of the tumor sample.
  • the IHC assay uses the anti-PD-L1 antibody 22C3.
  • the IHC assay is the pharmDx 22C3 IHC assay.
  • the PD-L1-positive tumor cell fraction is greater than, or equal to, 50% as determined by positive staining with the anti-PD-L1 antibody 22C3.
  • the tumor sample has been determined to have a combined positive score (CPS) of greater than, or equal to, 10 or a tumor proportion score (TPS) of greater than or equal to 1% in the tumor sample, e.g., as determined using the anti-PD-L1 antibody 22C3 as part of the pharmDx 22C3 IHC assay.
  • CPS combined positive score
  • TPS tumor proportion score
  • the tumor sample has been determined to have a CPS of greater than, or equal to, 10 or a TPS of greater than or equal to 1% and less than 50% in the tumor sample, e.g., as determined using the anti-PD-L1 antibody 22C3 as part of the pharmDx 22C3 IHC assay. In some embodiments, the tumor sample has been determined to have a CPS of greater than, or equal to, 20 or a TPS of greater than or equal to 50% in the tumor sample, e.g., as determined using the anti-PD-L1 antibody 22C3 as part of the pharmDx 22C3 IHC assay.
  • tumor samples that have been determined to have a CPS of greater than, or equal to, 1 are comparable to a TIC of greater than, or equal to, 5%.
  • the IHC assay uses the anti-PD-L1 antibody 28-8.
  • the IHC assay is the pharmDx 28-8 IHC assay.
  • the PD-L1-positive tumor cell fraction is greater than, or equal to, 50% as determined by positive staining with the anti-PD-L1 antibody 28-8.
  • a tumor sample obtained from the individual has a detectable nucleic acid expression level of PD-L1.
  • the detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technique, ISH, or a combination thereof.
  • the sample is selected from the group consisting of a tissue sample, a whole blood sample, a serum sample, and a plasma sample.
  • the tissue sample is a tumor sample.
  • the tumor sample comprises tumor-infiltrating immune cells, tumor cells, stromal cells, and any combinations thereof. III.
  • TIRAGOLUMAB AND ATEZOLIZUMAB Tiragolumab an anti-TIGIT antagonist antibody
  • atezolizumab an anti-PD-L1 antibody
  • NSCLC non-small cell lung cancer
  • Tiragolumab (CAS Registry Number: 1918185-84-8) is a fully human IgG1/kappa MAb that binds TIGIT and comprises the heavy chain sequence of SEQ ID NO: 4 and the light chain sequence of SEQ ID NO: 5.
  • Tiragolumab comprises two N-linked glycosylation sites (N306) in the Fc domain.
  • Tiragolumab is described in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Proposed INN: List 117, Vol.31, No.2, published June 9, 2017 (see page 343).
  • Tiragolumab (Genentech) is also known as MTIG7192A, RG6058, or RO7092284. Tiragolumab is described in PCT Pub.
  • Atezolizumab is an anti-PD-L1 antagonist monoclonal antibody (mAb) having the International Nonproprietary Names for Pharmaceutical Substances (INN) List 112 (WHO Drug Information, Vol.28, No.4, 2014, p.488), or the CAS Registry Number 1380723-44-3. C.
  • mAb monoclonal antibody
  • compositions utilized in the methods described herein can be administered by any suitable method, including, for example, intravenously, intramuscularly, subcutaneously, intradermally, percutaneously, intraarterially, intraperitoneally, intralesionally, intracranially, intraarticularly, intraprostatically, intrapleurally, intratracheally, intrathecally, intranasally, intravaginally, intrarectally, topically, intratumorally, peritoneally, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, intraorbitally, orally, topically, transdermally, intravitreally (e.g., by intravitreal injection), by eye drop, by inhalation, by injection, by implantation, by infusion, by continuous infusion, by localized perfusion bathing target cells directly, by catheter, by lavage, in cremes, or
  • compositions utilized in the methods described herein can also be administered systemically or locally.
  • the method of administration can vary depending on various factors (e.g., the compound or composition being administered and the severity of the condition, disease, or disorder being treated).
  • tiragolumab and/or atezolizumab is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.
  • Dosing can be by any suitable route, e.g., by injections, such as intravenous or subcutaneous injections, depending in part on whether the administration is brief or chronic.
  • Tiragolumab and/or atezolizumab may be formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • Tiragolumab and/or atezolizumab need not be, but are optionally formulated with and/or administered concurrently with one or more agents currently used to prevent or treat the disorder in question, e.g., one or more of the agents provided herein.
  • the effective amount of such other agents depends on the amount of tiragolumab or atezolizumab present in the formulation, the type of disorder or treatment, and other factors discussed above. These are generally used in the same dosages and with administration routes as described herein, or about from 1 to 99% of the dosages described herein, or in any dosage and by any route that is empirically/clinically determined to be appropriate.
  • the appropriate dosage of tiragolumab and atezolizumab, or any combination thereof, described herein will depend on the type of disease to be treated, the severity and course of the disease, whether the tiragolumab and/or atezolizumab is administered for preventive or therapeutic purposes, previous therapy, the patient’s clinical history and response to the tiragolumab and/or atezolizumab, and the discretion of the attending physician.
  • Tiragolumab and/or atezolizumab is suitably administered to the patient at one time or over a series of treatments.
  • One typical daily dosage might range from about 1 ⁇ g/kg to 100 mg/kg or more, depending on the factors mentioned above.
  • the treatment would generally be sustained until a desired suppression of disease symptoms occurs.
  • Such doses may be administered intermittently, e.g., every week or every three weeks (e.g., such that the patient receives, for example, from about two to about twenty, or e.g., about six doses of the tiragolumab and/or atezolizumab).
  • An initial higher loading dose, followed by one or more lower doses may be administered.
  • other dosage regimens may be useful. The progress of this therapy is easily monitored by conventional techniques and assays.
  • Dosing i.
  • tiragolumab is administered in a dose of about 0.01 to about 45 mg/kg, about 0.01 to about 40 mg/kg, about 0.01 to about 35 mg/kg, about 0.01 to about 30 mg/kg, about 0.01 to about 25 mg/kg, about 0.01 to about 20 mg/kg, about 0.01 to about 15 mg/kg, about 0.01 to about 10 mg/kg, about 0.01 to about 5 mg/kg, or about 0.01 to about 1 mg/kg administered daily, weekly, every two weeks, every three weeks, or every four weeks, for example.
  • tiragolumab is administered in a dose of 0.01 to 45 mg/kg, 0.01 to 40 mg/kg, 0.01 to 35 mg/kg, 0.01 to 30 mg/kg, 0.01 to 25 mg/kg, 0.01 to 20 mg/kg, 0.01 to 15 mg/kg, 0.01 to 10 mg/kg, 0.01 to 5 mg/kg, or 0.01 to 1 mg/kg administered daily, weekly, every two weeks, every three weeks, or every four weeks, for example.
  • Such dosing regimens can be utilized in treatments for subjects having relatively low body weight (e.g., 40 kg or less (e.g., from 5 kg to 40 kg, from 15 kg to 40 kg, or from 5 kg to 15 kg)) and have been developed through biosimulation studies based on extrapolations of pharmacokinetic parameters estimated from adult data.
  • the effective amount of tiragolumab to treat a subject having a cancer is a tiered dose based on a subject’s body weight.
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body weight, wherein the subject has a body weight of (a) less than or equal to 15 kg, and tiragolumab is administered at a dose of between about 10 mg to about 1000 mg every three weeks (e.g., about 300 mg every three weeks); (b) greater than 15 kg and less than or equal to 40 kg, and tiragolumab is administered at a dose of between about 10 mg to about 1000 mg every three weeks (e.g., about 400 mg every three weeks); or (c) greater than 40 kg, and tiragolumab is administered at a dose of between about 30 mg to about 1200 mg every three weeks (e.g., about 600 mg every three weeks).
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body weight, wherein the subject has a body weight of (a) less than or equal to 15 kg, and tiragolumab is administered at a dose of about 300 mg every three weeks; (b) greater than 15 kg and less than or equal to 40 kg, and tiragolumab is administered at a dose of about 400 mg every three weeks; or (c) greater than 40 kg, and tiragolumab is administered at a dose of about 600 mg every three weeks.
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body weight, wherein the subject has a body weight of (a) less than or equal to 15 kg, and tiragolumab is administered at a dose of between 10 mg to 1000 mg every three weeks (e.g., 300 mg every three weeks); (b) greater than 15 kg and less than or equal to 40 kg, and tiragolumab is administered at a dose of between 10 mg to 1000 mg every three weeks (e.g., 400 mg every three weeks); or (c) greater than 40 kg, and tiragolumab is administered at a dose of between 30 mg to 1200 mg every three weeks (e.g., 600 mg every three weeks).
  • the effective amount of tiragolumab is a tiered dose based on PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO a subject’s body weight, wherein the subject has a body weight of (a) less than or equal to 15 kg, and tiragolumab is administered at a dose of 300 mg every three weeks; (b) greater than 15 kg and less than or equal to 40 kg, and tiragolumab is administered at a dose of 400 mg every three weeks; or (c) greater than 40 kg, and tiragolumab is administered at a dose of 600 mg every three weeks.
  • the effective amount of tiragolumab is a dose of between about 30 mg to about 1200 mg (e.g., between about 30 mg to about 1100 mg, e.g., between about 60 mg to about 1000 mg, e.g., between about 100 mg to about 900 mg, e.g., between about 200 mg to about 800 mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to about 800 mg, e.g., between about 400 mg to about 750 mg, e.g., between about 450 mg to about 750 mg, e.g., between about 500 mg to about 700 mg, e.g., between about 550 mg to about 650 mg, e.g., 600 mg ⁇ 10 mg, e.g., 600 ⁇ 6 mg, e.g., 600 ⁇ 5 mg, e.g., 600 ⁇ 3 mg, e.g., 600 ⁇ 1 mg, e.g., 600 ⁇
  • the effective amount of tiragolumab is a dose of about 600 mg every three weeks for subject with a body weight greater than 40 kg. In some instances, the effective amount of tiragolumab is a dose of between 30 mg to 1200 mg (e.g., between 30 mg to 1100 mg, e.g., between 60 mg to 1000 mg, e.g., between 100 mg to 900 mg, e.g., between 200 mg to 800 mg, e.g., between 300 mg to 800 mg, e.g., between 400 mg to 800 mg, e.g., between 400 mg to 750 mg, e.g., between 450 mg to 750 mg, e.g., between 500 mg to 700 mg, e.g., between 550 mg to 650 mg, e.g., 600 mg ⁇ 10 mg, e.g., 600 ⁇ 6 mg, e.g., 600 ⁇ 5 mg, e.g., 600 ⁇ 3 mg, e.g.,
  • the effective amount of tiragolumab is a dose of 600 mg every three weeks for subject with a body weight greater than 40 kg. In some instances, the effective amount of tiragolumab is a dose of between about 10 mg to about 1000 mg (e.g., between about 20 mg to about 1000 mg, e.g., between about 50 mg to about 900 mg, e.g., between about 100 mg to about 850 mg, e.g., between about 200 mg to about 700 mg, e.g., between about 250 mg to about 600 mg, e.g., between about 300 mg to about 500 mg, e.g., between about 350 mg to about 450 mg, e.g., between about 390 mg to about 410 mg, e.g., about 400 mg) every three weeks (Q3W) for subject with a body weight greater than 15 kg and less than or equal to 40 kg (e.g., 15.1 kg, 15.2 kg, 15.3 kg, 15.4 kg, 15.5 kg, 16 kg, 17
  • the effective amount of tiragolumab is a dose of about 400 mg every three weeks (e.g., 400 mg ⁇ 10 mg, e.g., 400 ⁇ 6 mg, e.g., 400 ⁇ 5 mg, e.g., 400 ⁇ 3 mg, e.g., 400 ⁇ 1 mg, e.g., 400 ⁇ 0.5 mg, e.g., 400 mg every three weeks) for subject with a body weight greater than 15 kg and less than or equal to 40 kg.
  • a body weight greater than 15 kg and less than or equal to 40 kg.
  • the effective amount of tiragolumab is a dose of between 10 mg to 1000 mg (e.g., between 20 mg to 1000 mg, e.g., between 50 mg to 900 mg, e.g., PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO between 100 mg to 850 mg, e.g., between 200 mg to 700 mg, e.g., between 250 mg to 600 mg, e.g., between 300 mg to 500 mg, e.g., between 350 mg to 450 mg, e.g., between 390 mg to 410 mg, e.g., 400 mg) every three weeks (Q3W) for subject with a body weight greater than 15 kg and less than or equal to 40 kg (e.g., 15.1 kg, 15.2 kg, 15.3 kg, 15.4 kg, 15.5 kg, 16 kg, 17 kg, 18 kg, 19 kg, 20 kg, 21 kg, 22 kg, 23 kg, 24 kg,
  • the effective amount of tiragolumab is a dose of 400 mg every three weeks (e.g., 400 mg ⁇ 10 mg, e.g., 400 ⁇ 6 mg, e.g., 400 ⁇ 5 mg, e.g., 400 ⁇ 3 mg, e.g., 400 ⁇ 1 mg, e.g., 400 ⁇ 0.5 mg, e.g., 400 mg every three weeks) for subject with a body weight greater than 15 kg and less than or equal to 40 kg.
  • the effective amount of tiragolumab is a dose of between about 10 mg to about 1000 mg (e.g., between about 10 mg to about 900 mg, e.g., between about 50 mg to about 900 mg, e.g., between about 100 mg to about 750 mg, e.g., between about 100 mg to about 600 mg, e.g., between about 150 mg to about 500 mg, e.g., between about 200 mg to about 400 mg, e.g., between about 250 mg to about 350 mg, e.g., between about 290 mg to about 310 mg, e.g., about 300 mg) every three weeks (Q3W) for subject with a body weight less than or equal to 15 kg (e.g., 0.5 kg, 1 kg, 1.5 kg, 2.0 kg, 2.5 kg, 3.0 kg, 3.5 kg, 4.0 kg, 4.5 kg, 5.0 kg, 5.5 kg, 6.0 kg, 6.5 kg, 7.0 kg, 7.5 kg, 8.0 kg, 8.5 kg, 9.
  • the effective amount of tiragolumab is a dose of about 300 mg every three weeks (e.g., 300 mg ⁇ 10 mg, e.g., 300 ⁇ 6 mg, e.g., 300 ⁇ 5 mg, e.g., 300 ⁇ 3 mg, e.g., 300 ⁇ 1 mg, e.g., 300 ⁇ 0.5 mg, e.g., 300 mg every three weeks) for subject with a body weight less than or equal to 15 kg.
  • the effective amount of tiragolumab is a dose of between 10 mg to 1000 mg (e.g., between 10 mg to 900 mg, e.g., between 50 mg to 900 mg, e.g., between 100 mg to 750 mg, e.g., between 100 mg to 600 mg, e.g., between 150 mg to 500 mg, e.g., between 200 mg to 400 mg, e.g., between 250 mg to 350 mg, e.g., between 290 mg to 310 mg, e.g., 300 mg) every three weeks (Q3W) for subject with a body weight less than or equal to 15 kg (e.g., 0.5 kg, 1 kg, 1.5 kg, 2.0 kg, 2.5 kg, 3.0 kg, 3.5 kg, 4.0 kg, 4.5 kg, 5.0 kg, 5.5 kg, 6.0 kg, 6.5 kg, 7.0 kg, 7.5 kg, 8.0 kg, 8.5 kg, 9.0 kg, 9.5 kg, 10.0 kg, 10.5 kg, 11.0 kg,
  • the effective amount of tiragolumab is a dose of 300 mg every three weeks (e.g., 300 mg ⁇ 10 mg, e.g., 300 ⁇ 6 mg, e.g., 300 ⁇ 5 mg, e.g., 300 ⁇ 3 mg, e.g., 300 ⁇ 1 mg, e.g., 300 ⁇ 0.5 mg, e.g., 300 mg every three weeks) for subject with a body weight less than or equal to 15 kg.
  • the effective amount of tiragolumab to treat a subject having a cancer is a tiered dose based on a subject’s body surface area.
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body surface area, wherein the subject has a body surface area of (a) less than or equal to 0.5 m 2 , and tiragolumab is administered at a dose of between about 10 mg to about 1000 mg every three weeks (e.g., about 300 mg every three weeks); (b) greater than 0.5 m 2 and less than or equal to 0.75 m 2 , and tiragolumab is administered at a dose of between about 10 mg to about 1000 mg every three weeks (e.g., about 350 mg every three weeks); (c) greater than 0.75 m 2 and less than or equal to 1.25 m 2 , and tiragolumab is administered at a dose of between about 10 mg to about 1000 mg every three weeks (e.g., about 450 mg every three weeks); or (d) greater than 1.25 m 2 , and tiragolumab is administered at a dose of between about 30 mg to about 1200 mg
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body surface area, wherein the subject has a body surface area of (a) less than or equal to 0.5 m 2 , and tiragolumab is administered at a dose of between about 250 mg to about 350 mg every three weeks (e.g., about 300 mg every three weeks); (b) greater than 0.5 m 2 and less than or equal to 0.75 m 2 , and tiragolumab is administered at a dose of between about 300 mg to about 400 mg every three weeks (e.g., about 350 mg every three weeks); or (c) greater than 0.75 m 2 and less than or equal to 1.25 m 2 , and tiragolumab is administered at a dose of between about 400 mg to about 500 mg every three weeks (e.g., about 450 mg every three weeks); or (d) greater than 1.25 m 2 , and tiragolumab is administered at a dose of between about 550 mg to about
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body surface area, wherein the subject has a body surface area of (a) less than or equal to 0.5 m 2 , and tiragolumab is administered at a dose of about 300 mg every three weeks; (b) greater than 0.5 m 2 and less than or equal to 0.75 m 2 , and tiragolumab is administered at a dose of about 400 mg every three weeks; (c) greater than 0.75 m 2 and less than or equal to 1.25 m 2 , and tiragolumab is administered at a dose of 450 mg every three weeks; or (d) greater than 1.25 m 2 , and tiragolumab is administered at a dose of about 600 mg every three weeks.
  • the effective amount of tiragolumab to treat a subject having a cancer is a tiered dose based on a subject’s body surface area.
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body surface area, wherein the subject has a body surface area of (a) less than or equal to 0.5 m 2 , and tiragolumab is administered at a dose of between 10 mg to 1000 mg every three weeks (e.g., 300 mg every three weeks); (b) greater than 0.5 m 2 and less than or equal to 0.75 m 2 , and tiragolumab is administered at a dose of between 10 mg to 1000 mg every three weeks (e.g., 350 mg every three weeks); (c) greater than 0.75 m 2 and less than or equal to 1.25 m 2 , and tiragolumab is administered at a dose of between 10 mg to 1000 mg every three weeks (e.g., 450 mg every three weeks); or (d)
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body surface area, wherein the subject has a body surface area of (a) less than or equal to 0.5 m 2 , and tiragolumab is administered at a dose of between 250 mg to 350 mg every three weeks (e.g., 300 mg every three weeks); (b) greater than 0.5 m 2 and less than or equal to 0.75 m 2 , and tiragolumab is administered at a dose of between 300 mg to 400 mg every three weeks (e.g., 350 mg every three weeks); or (c) greater than 0.75 m 2 and less than or equal to 1.25 m 2 , and tiragolumab is administered at a dose of between 400 mg to 500 mg every three weeks (e.g., 450 mg every three weeks); or (d) greater than 1.25 m 2 , and tiragolumab is administered at a dose of between 550 mg to 650 mg every three weeks (e.g.,
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body surface area, wherein the subject has a body surface area of (a) less than or equal to 0.5 m 2 , and tiragolumab is administered at a dose of 300 mg every three weeks; (b) greater than 0.5 m 2 and less than or equal to 0.75 m 2 , and tiragolumab is administered at a dose of 400 mg every three weeks; (c) greater than 0.75 m 2 and less than or equal to 1.25 m 2 , and tiragolumab is administered at a dose of 450 mg every three weeks; or (d) greater than 1.25 m 2 , and tiragolumab is administered at a dose of 600 mg every three weeks.
  • the effective amount of tiragolumab is a dose of between about 30 mg to about 1200 mg (e.g., between about 30 mg to about 1100 mg, e.g., between about 60 mg to about 1000 mg, e.g., between about 100 mg to about 900 mg, e.g., between about 200 mg to about 800 mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to about 800 mg, e.g., between about 400 mg to about 750 mg, e.g., between about 450 mg to about 750 mg, e.g., between about 500 mg to about 700 mg, e.g., between about 550 mg to about 650 mg, e.g., 600 mg ⁇ 10 mg, e.g., 600 ⁇ 6 mg, e.g., 600 ⁇ 5 mg,
  • the effective amount of tiragolumab is a dose of about 600 mg every three weeks for subject with a body surface area greater than 1.25 m 2 .
  • the effective amount of tiragolumab is a dose of between 30 mg to 1200 mg (e.g., between 30 mg to 1100 mg, e.g., between 60 mg to 1000 mg, e.g., between 100 mg to 900 mg, e.g., between 200 mg to 800 mg, e.g., between 300 mg to 800 mg, e.g., between 400 mg to 800 mg, e.g., between 400 mg to 750 mg, e.g., between 450 mg to 750 mg, e.g., between 500 mg to 700 mg, e.g., between 550 mg to 650 mg, e.g., 600 mg ⁇ 10 mg, e.g., 600 ⁇ 6 mg, e.g., 600 ⁇ 5 mg, e.g., 600 ⁇ 3 mg,
  • the effective amount of tiragolumab is a dose of 600 mg every three weeks for subject with a body surface area greater than 1.25 m 2 .
  • the effective amount of tiragolumab is a dose of between about 10 mg to about 1000 mg (e.g., between about 20 mg to about 1000 mg, e.g., between about 50 mg to about 900 mg, e.g., between about 100 mg to about 850 mg, e.g., between about 200 mg to about 700 mg, e.g., between about 250 mg to about 600 mg, e.g., between about 300 mg to about 500 mg, e.g., between about 400 mg to about 500 mg, e.g., between about 440 mg to about 460 mg, e.g., about 450 mg) every three weeks (Q3W) for subject with a body surface area greater than 0.75 m 2 and less than or equal to 1.25 m 2 (e.g., 0.76 m 2 , 0.77 m 2
  • the effective amount of tiragolumab is a dose of about 450 mg every three weeks (e.g., 450 mg ⁇ 10 mg, e.g., 450 ⁇ 6 mg, e.g., 450 ⁇ 5 mg, e.g., 450 ⁇ 3 mg, e.g., 450 ⁇ 1 mg, e.g., 450 ⁇ 0.5 mg, e.g., 450 mg every three weeks) for subject with a body surface area greater than 0.75 m 2 and less than or equal to 1.25 m 2 .
  • the effective amount of tiragolumab is a dose of between about 10 mg to about 1000 mg (e.g., between about 20 mg to about 1000 mg, e.g., between about 50 mg to about 900 mg, e.g., between about 100 mg to about 850 mg, e.g., between about 200 mg to about 700 mg, e.g., between about 250 mg to about 600 mg, e.g., between about 300 mg to about 500 mg, e.g., between about 300 mg to about 400 mg, e.g., between about 340 mg to about 360 mg, e.g., about 350 mg) every three weeks (Q3W) for subject with a body surface area greater than 0.5 m 2 and less than or equal to 0.75 m 2 (e.g., 0.51 m 2 , 0.52 m 2 , 0.53 m 2 , 0.54 m 2 , 0.55 m 2 , 0.56 m 2 , 0.57 m 2 , 0.58 m 2
  • the effective amount of tiragolumab is a dose of about 350 mg every three weeks (e.g., 350 mg ⁇ 10 mg, e.g., 350 ⁇ 6 mg, e.g., 350 ⁇ 5 mg, e.g., 350 ⁇ 3 mg, e.g., 350 ⁇ 1 mg, e.g., 350 ⁇ 0.5 mg, e.g., 350 mg every three weeks) for subject with a body surface area greater than 0.5 m 2 and less than or equal to 0.75 m 2 .
  • the effective amount of tiragolumab is a dose of between about 10 mg to about 1000 mg (e.g., between about 10 mg to about 900 mg, e.g., between about 50 mg to about 900 mg, e.g., between about 100 mg to about 750 mg, e.g., between about 100 mg to about 600 mg, e.g., between about 150 mg to about 500 mg, e.g., between about 200 mg to about 400 mg, e.g., between about 250 mg to about 350 mg, e.g., between about 290 mg to about 310 mg, e.g., about 300 mg) every three weeks (Q3W) for subject with a body surface area less than or equal to 0.5 m 2 (e.g., 0.02 m 2 , 0.04 m 2 , 0.06 m 2 , 0.08 m 2 , 0.1 m 2 , 0.15 m 2 , 0.20 m 2 , 0.25 m 2 , 0.30 m 2
  • the effective amount of tiragolumab is a dose of about 300 mg every three weeks (e.g., 300 mg ⁇ 10 mg, e.g., 300 ⁇ 6 mg, e.g., 300 ⁇ 5 mg, e.g., 300 ⁇ 3 mg, e.g., 300 ⁇ 1 mg, e.g., 300 ⁇ 0.5 mg, e.g., 300 mg every three weeks) for subject with a body surface area less than or equal to 0.5 m 2 .
  • the effective amount of tiragolumab is a dose (e.g., a fixed dose) of between about 10 mg to about 1000 mg (e.g., between about 20 mg to about 1000 mg, e.g., between about 50 mg to about 900 mg, e.g., between about 100 mg to about 850 mg, e.g., between about 200 mg to about 800 mg, e.g., between about 300 mg to about 600 mg, e.g., between about 400 mg to about 500 mg, e.g., between about 405 mg to about 450 mg, e.g., between about 410 mg to about 430 mg, e.g., about 420 mg) every two weeks (Q2W).
  • a dose e.g., a fixed dose of between about 10 mg to about 1000 mg (e.g., between about 20 mg to about 1000 mg, e.g., between about 50 mg to about 900 mg, e.g., between about 100 mg to about 850 mg, e.g
  • the effective amount of tiragolumab is a dose of about 420 mg every two weeks (e.g., 420 mg ⁇ 10 mg, e.g., 420 ⁇ 6 mg, e.g., 420 ⁇ 5 mg, e.g., 420 ⁇ 3 mg, e.g., 420 ⁇ 1 mg, e.g., 420 ⁇ 0.5 mg, e.g., 420 mg every two weeks).
  • the method comprises administering to the subject or population of subjects tiragolumab at a dose of about 300 mg to about 600 mg every two weeks.
  • the method comprises administering to the subject or population of subjects tiragolumab at a dose of 300 mg to 600 mg every two weeks. In some instances, the method comprises administering to the subject or population of subjects tiragolumab at a dose of about 420 every two weeks. In some instances, the method comprises administering to the subject or population of subjects tiragolumab at a dose of 420 every two weeks. In some instances, the dose of tiragolumab is a fixed dose.
  • the effective amount of tiragolumab is a dose (e.g., a fixed dose) of between about 30 mg to about 1200 mg (e.g., between about 30 mg to about 1100 mg, e.g., between about 60 mg to about 1000 mg, e.g., between about 100 mg to about 900 mg, e.g., between about 200 mg to about 800 mg, e.g., between about 300 mg to about 800 mg, e.g., between about 400 mg to about 800 mg, e.g., between about 400 mg to about 800 mg, e.g., between about 400 mg to about 750 mg, e.g., between about 450 mg to about 750 mg, e.g., between about 500 mg to about 700 mg, e.g., between about 550 mg to about 650 mg, e.g., 600 mg ⁇ 10 mg, e.g., 600 ⁇ 6 mg, e.g., 600 ⁇ 5 mg, e.g., 600 ⁇ 3
  • the effective amount of tiragolumab is a dose of about 600 mg every three weeks.
  • the method comprises administering to the subject or population of subjects tiragolumab at a dose of about 600 every three weeks.
  • the method PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO comprises administering to the subject or population of subjects tiragolumab at a dose of 600 mg every three weeks.
  • the dose of tiragolumab is a fixed dose.
  • the effective amount of tiragolumab is a dose of between about 200 mg to about 2000 mg (e.g., between about 200 mg to about 2000 mg, e.g., between about 400 mg to about 1900 mg, e.g., between about 500 mg to about 1800 mg, e.g., between about 600 mg to about 1700 mg, e.g., between about 700 mg to about 1400 mg, e.g., between about 800 mg to about 1600 mg, e.g., between about 900 mg to about 1500 mg, e.g., between about 1000 mg to about 1400 mg, e.g., between about 1050 mg to about 1350 mg, e.g., between about 1100 mg to about 1300 mg, e.g., between about 1150 mg to about 1250 mg, e.g., between about 1175 mg to about 1225 mg, e.g., between about 1190 mg to about 1210 mg, e.g., about 1200 mg, e.g., 1200 mg,
  • the effective amount of tiragolumab is a dose of about 600 mg every three weeks. In some instances, the effective amount of tiragolumab is a dose of 600 mg every three weeks. In some instances, the effective amount of tiragolumab is a dose of between about 200 mg to about 2000 mg (e.g., between about 200-300 mg, between about 300-400 mg, between about 400-500 mg, between about 500-600 mg, between about 600-700 mg, between about 700-800 mg, between about 800-900 mg, between about 900-1000 mg, between about 1000-1100 mg, between about 1100-1200 mg, between about 1200-1300 mg, between about 1300-1400 mg, between about 1400-1500 mg, between about 1500-1600 mg, between about 1600-1700 mg, between about 1700-1800 mg, between about 1800-1900 mg, or between about 1900-2000 mg, e.g., between about 200 mg to about 1600 mg, e.g., between about 250 mg to about 1600 mg, e.g., between about 300
  • the effective amount of tiragolumab is about 700 mg to about 1000 mg every four weeks. In some instances, the effective amount of tiragolumab is 700 mg to 1000 mg every four weeks. In some instances, the effective amount of tiragolumab is about 840 mg every four weeks. In some instances, the effective amount of tiragolumab is 840 mg every four weeks.
  • the 840 mg Q4W dosing regimen is supported by results from PK modeling and simulation and exposure-safety analyses. Briefly, the average concentration following the 840 mg Q4W dosing regimen is similar to that of the 600 mg every 3 weeks dosing regimen, which was evaluated in previous studies.
  • the Cmax of the 840 mg Q4W dosing regimen was simulated to be 28% higher at steady state, relative to the Cmax for the 600 mg every 3 weeks dosing regimen, but falls within the range of observed exposure of the highest administered dose in the clinic (1200 mg every 3 weeks).
  • a preliminary analysis of the tiragolumab exposure-safety PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO relationship based on previous observations (tiragolumab doses of 2 ⁇ 1200 mg every 3 weeks administered as monotherapy or in combination with atezolizumab 1200 mg every 3 weeks) suggest that tiragolumab exhibits a flat exposure-safety relationship.
  • the 840 mg Q4W dosing regimen can provide comparable safety and efficacy as the 600 mg every-3-weeks dosing regimen, given that the predicted exposure is within the range of observed efficacious exposures and tiragolumab exhibits a flat exposure-safety relationship.
  • the effective amount of tiragolumab is a dose of between about 200 mg to about 2000 mg (e.g., between about 200 mg to about 2000 mg, e.g., between about 400 mg to about 1900 mg, e.g., between about 500 mg to about 1800 mg, e.g., between about 600 mg to about 1700 mg, e.g., between about 700 mg to about 1400 mg, e.g., between about 800 mg to about 1600 mg, e.g., between about 900 mg to about 1500 mg, e.g., between about 1000 mg to about 1400 mg, e.g., between about 1050 mg to about 1350 mg, e.g., between about 1100 mg to about 1300 mg, e.g., between about 1150 mg to about 1250 mg, e.g., between about 1175 mg to about 1225 mg, e.g., between about 1190 mg to about 1210 mg (e.g., between 200 mg to 2000 mg, e.g., between about 400 mg
  • the effective amount of tiragolumab is a dose of about 840 mg every four weeks (e.g., 840 mg ⁇ 10 mg, e.g., 840 ⁇ 6 mg, e.g., 840 ⁇ 5 mg, e.g., 840 ⁇ 3 mg, e.g., 840 ⁇ 1 mg, e.g., 840 ⁇ 0.5 mg, e.g., 840 mg every four weeks).
  • the effective amount of tiragolumab is a dose of 840 mg every four weeks.
  • the dose of tiragolumab is a fixed dose.
  • the effective amount of tiragolumab is a dose of about 1200 mg every four weeks.
  • the dose of tiragolumab administered in a combination therapy may be reduced as compared to a standard dose of tiragolumab administered as a monotherapy.
  • tiragolumab is administered intravenously.
  • tiragolumab is administered subcutaneously.
  • tiragolumab is administered to the patient intravenously at a dose of about 420 mg every 2 weeks, about 600 mg every 3 weeks, or about 840 mg of every 4 weeks.
  • tiragolumab is administered to the patient intravenously at a dose of 420 mg every 2 weeks, 600 mg every 3 weeks, or 840 mg of every 4 weeks.
  • a subject is administered a total of 1 to 20 doses of tiragolumab, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 doses.
  • a subject is administered a total of 1 to 50 doses of tiragolumab, e.g., 1 to 50 doses, 1 to 45 doses, 1 to 40 doses, 1 to 35 doses, 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 50 doses, 2 to 45 doses, 2 to 40 doses, 2 to 35 doses, 2 to 30 doses, 2 to 25 doses, 2 to 20 doses, 2 to 15 doses, 2 to 10 doses, 2 to 5 doses, 3 to 50 doses, 3 to 45 doses, 3 to 40 doses, 3 to 35 doses, 3 to 30 PATENT Attorney Docket No.: 50474-320WO2 Genentech
  • the doses may be administered intravenously.
  • the therapeutically effective amount of atezolizumab to a human will be in the range of about 0.01 to about 50 mg/kg of patient body weight, whether by one or more administrations.
  • Atezolizumab is administered in a dose of about 0.01 to about 45 mg/kg, about 0.01 to about 40 mg/kg, about 0.01 to about 35 mg/kg, about 0.01 to about 30 mg/kg, about 0.01 to about 25 mg/kg, about 0.01 to about 20 mg/kg, about 0.01 to about 15 mg/kg, about 0.01 to about 10 mg/kg, about 0.01 to about 5 mg/kg, or about 0.01 to about 1 mg/kg administered daily, weekly, every two weeks, every three weeks, or every four weeks, for example.
  • Atezolizumab is administered in a dose of 0.01 to 45 mg/kg, 0.01 to 40 mg/kg, 0.01 to 35 mg/kg, 0.01 to 30 mg/kg, 0.01 to 25 mg/kg, 0.01 to 20 mg/kg, 0.01 to 15 mg/kg, 0.01 to 10 mg/kg, 0.01 to 5 mg/kg, or 0.01 to 1 mg/kg administered daily, weekly, every two weeks, every three weeks, or every four weeks, for example.
  • atezolizumab is administered on about Day 1 (e.g., Day -3, Day -2, Day -1, Day 1, Day 2, or Day 3) of a dosing cycle.
  • the effective amount of atezolizumab is a dose (e.g., a fixed dose) of between about 20 mg to about 1600 mg (e.g., between about 40 mg to about 1500 mg, e.g., between about 200 mg to about 1400 mg, e.g., between about 300 mg to about 1400 mg, e.g., between about 400 mg to about 1400 mg, e.g., between about 500 mg to about 1300 mg, e.g., between about 600 mg to about 1200 mg, e.g., between about 700 mg to about 1100 mg, e.g., between about 800 mg to about 1000 mg, e.g., between about 800 mg to about 900 mg, e.g., about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, or about 900 mg) every two weeks (Q2W).
  • a dose e.g., a fixed dose of between about 20
  • the effective amount of atezolizumab is a dose (e.g., a fixed dose) of between 20 mg to 1600 mg (e.g., between 40 mg to 1500 mg, e.g., between 200 mg to 1400 mg, e.g., between 300 mg to 1400 mg, e.g., between 400 mg to 1400 mg, e.g., between 500 mg to 1300 mg, e.g., between 600 mg to 1200 mg, e.g., between 700 mg to 1100 mg, e.g., between 800 mg to 1000 mg, e.g., between 800 mg to 900 mg, e.g., 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, or 900 mg) every two weeks (Q2W).
  • a dose e.g., a fixed dose of between 20 mg to 1600 mg (e.g., between 40 mg to 1500 mg, e.g., between 200 mg to 1400 mg,
  • the effective amount of atezolizumab is a dose of about 840 mg every two weeks (e.g., 840 mg ⁇ 10 mg, e.g., 840 ⁇ 6 mg, e.g., 840 ⁇ 5 mg, e.g., 840 ⁇ 3 mg, e.g., 840 ⁇ 1 mg, e.g., 840 ⁇ 0.5 PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO mg, e.g., 840 mg every two weeks). In some instances, the effective amount of atezolizumab is a dose of about 840 mg every two weeks.
  • the effective amount of atezolizumab is a dose of between about 0.01 mg/kg to about 50 mg/kg of the subject’s body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g., between about 0.1 mg/kg to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g., between about 2.5 mg/kg to about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between about 5 mg/kg to about 15 mg/kg, e.g., between about 7.5 mg/kg to about 12.5 mg/kg, e.g., about 10 ⁇ 2 mg/kg, about 10 ⁇ 1 mg/kg, about 10 ⁇ 0.5 mg/kg, about 10 ⁇ 0.2 mg/kg, or about 10 ⁇ 0.1 mg/kg, e.g., about 10 mg/kg) every two weeks.
  • body weight e.g., between
  • the effective amount of atezolizumab is a dose of between about 0.01 mg/kg to about 10 mg/kg of the subject’s body weight (e.g., between about 0.1 mg/kg to about 10 mg/kg, e.g., between about 0.5 mg/kg to about 10 mg/kg, e.g., between about 1 mg/kg to about 10 mg/kg, e.g., between about 2.5 mg/kg to about 10 mg/kg, e.g., between about 5 mg/kg to about 10 mg/kg, e.g., between about 7.5 mg/kg to about 10 mg/kg, e.g., between about 8 mg/kg to about 10 mg/kg, e.g., between about 9 mg/kg to about 10 mg/kg, e.g., between about 9.5 mg/kg to about 10 mg/kg, e.g., about 10 ⁇ 1 mg/kg, e.g., about 10 ⁇ 0.5 mg/kg, e.g., about 10 ⁇
  • the effective amount of atezolizumab is a dose of between 0.01 mg/kg to 50 mg/kg of the subject’s body weight (e.g., between 0.01 mg/kg to 45 mg/kg, e.g., between 0.1 mg/kg to 40 mg/kg, e.g., between 1 mg/kg to 35 mg/kg, e.g., between 2.5 mg/kg to 30 mg/kg, e.g., between 5 mg/kg to 25 mg/kg, e.g., between 5 mg/kg to 15 mg/kg, e.g., between 7.5 mg/kg to 12.5 mg/kg, e.g., 10 ⁇ 2 mg/kg, 10 ⁇ 1 mg/kg, 10 ⁇ 0.5 mg/kg, 10 ⁇ 0.2 mg/kg, or 10 ⁇ 0.1 mg/kg, e.g., 10 mg/kg) every two weeks.
  • body weight e.g., between 0.01 mg/kg to 45 mg/kg, e.g., between 0.1 mg/
  • the effective amount of atezolizumab is a dose of between 0.01 mg/kg to 10 mg/kg of the subject’s body weight (e.g., between 0.1 mg/kg to 10 mg/kg, e.g., between 0.5 mg/kg to 10 mg/kg, e.g., between 1 mg/kg to 10 mg/kg, e.g., between 2.5 mg/kg to 10 mg/kg, e.g., between 5 mg/kg to 10 mg/kg, e.g., between 7.5 mg/kg to 10 mg/kg, e.g., between 8 mg/kg to 10 mg/kg, e.g., between 9 mg/kg to 10 mg/kg, e.g., between 9.5 mg/kg to 10 mg/kg, e.g., 10 ⁇ 1 mg/kg, e.g., 10 ⁇ 0.5 mg/kg, e.g., 10 ⁇ 0.2 mg/kg, e.g., 10 ⁇ 0.1 mg/kg, e
  • the effective amount of atezolizumab is a dose of about 10 mg/kg every two weeks. In some instances, the effective amount of atezolizumab is a dose of 10 mg/kg every two weeks. In some instances, the effective amount of atezolizumab to treat a subject having a cancer is a dose of between about 0.01 mg/kg to about 50 mg/kg of the subject’s body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g., between about 0.1 mg/kg to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g., between about 2.5 mg/kg to about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between about 10 mg/kg to about 20 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 ⁇ 2 mg/kg, about
  • the effective amount of atezolizumab is a dose of between about 0.01 mg/kg to about 15 mg/kg of the subject’s body weight (e.g., between about 0.1 mg/kg to about 15 mg/kg, e.g., between about 0.5 mg/kg to about 15 mg/kg, e.g., between about 1 mg/kg to about 15 mg/kg, e.g., between about 2.5 mg/kg to about 15 mg/kg, e.g., between about 5 mg/kg to about 15 mg/kg, e.g., between about 7.5 mg/kg to about PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO 15 mg/kg, e.g., between about 10 mg/kg to about 15 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., between about 14 mg/kg to about 15 mg/kg, e.g., about 15 mg/kg of
  • the effective amount of atezolizumab to treat a subject having a cancer is a dose of between 0.01 mg/kg to 50 mg/kg of the subject’s body weight (e.g., between 0.01 mg/kg to 45 mg/kg, e.g., between 0.1 mg/kg to 40 mg/kg, e.g., between 1 mg/kg to 35 mg/kg, e.g., between 2.5 mg/kg to 30 mg/kg, e.g., between 5 mg/kg to 25 mg/kg, e.g., between 10 mg/kg to 20 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., 15 ⁇ 2 mg/kg, 15 ⁇ 1 mg/kg, 15 ⁇ 0.5 mg/kg, 15 ⁇ 0.2 mg/kg, or 15 ⁇ 0.1 mg/kg, e.g., 15 mg/kg) every three weeks.
  • body weight e.g., between 0.01 mg/kg to 45 mg/kg, e.
  • the effective amount of atezolizumab is a dose of between 0.01 mg/kg to 15 mg/kg of the subject’s body weight (e.g., between 0.1 mg/kg to 15 mg/kg, e.g., between 0.5 mg/kg to 15 mg/kg, e.g., between 1 mg/kg to 15 mg/kg, e.g., between 2.5 mg/kg to 15 mg/kg, e.g., between 5 mg/kg to 15 mg/kg, e.g., between 7.5 mg/kg to 15 mg/kg, e.g., between 10 mg/kg to 15 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., between 14 mg/kg to 15 mg/kg, e.g., 15 ⁇ 1 mg/kg, e.g., 15 ⁇ 0.5 mg/kg, e.g., 15 ⁇ 0.2 mg/kg, e.g., 15 ⁇ 0.1 mg/kg, e
  • the effective amount of atezolizumab is a dose of about 15 mg/kg administered every three weeks. In some instances, the effective amount of atezolizumab is a dose of about 15 mg/kg administered every three weeks with a maximum dose of 1200 mg every three weeks. In some instances, the dose of atezolizumab administered in a combination therapy (e.g., a combination treatment with tiragolumab) may be reduced as compared to a standard dose of atezolizumab administered as a monotherapy. In some embodiments, atezolizumab is administered at a maximum dose of 1200 mg every three weeks.
  • a combination therapy e.g., a combination treatment with tiragolumab
  • atezolizumab is administered at a maximum dose of 1200 mg every three weeks.
  • the effective amount of atezolizumab is a dose of between about 80 mg to about 2000 mg (e.g., between about 100 mg to about 1600 mg, e.g., between about 200 mg to about 1600 mg, e.g., between about 300 mg to about 1600 mg, e.g., between about 400 mg to about 1600 mg, e.g., between about 500 mg to about 1600 mg, e.g., between about 600 mg to about 1600 mg, e.g., between about 700 mg to about 1600 mg, e.g., between about 800 mg to about 1600 mg, e.g., between about 900 mg to about 1500 mg, e.g., between about 1000 mg to about 1400 mg, e.g., between about 1050 mg to about 1350 mg, e.g., between about 1100 mg to about 1300 mg, e.g., between about 1150 mg to about 1250 mg, e.g., between about 1175 mg to about 1225 mg, e.g., between about
  • the effective amount of atezolizumab is a dose of about 1200 mg every three weeks (e.g., 1200 mg ⁇ 10 mg, e.g., 1200 ⁇ 6 mg, e.g., 1200 ⁇ 5 mg, e.g., 1200 ⁇ 3 mg, e.g., 1200 ⁇ 1 mg, e.g., 1200 ⁇ 0.5 mg, e.g., 1200 mg every three weeks). In some instances, the effective amount of atezolizumab is a dose of 1200 mg every three weeks.
  • the effective amount of atezolizumab is a dose of between about 10 mg and about 800 mg (e.g., between about 10 mg and about 800 mg, e.g., between about 20 mg and about 700 mg, e.g., between about 50 mg and about 600 mg, e.g., between about 75 mg and about 500 mg, e.g., between about 100 mg and about 400 mg, e.g., between about 100 mg and about 300 mg, e.g., between about 125 mg and about 275 mg, e.g., between about 150 mg and about 250 mg, e.g., between about 175 mg and about 225 mg, e.g., between about 190 mg and about 210 mg, e.g., about 200 mg ⁇ 10 mg, PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO e.g., 200 mg ⁇ 7.5 mg, e.g., 200 mg ⁇ 5 mg
  • the effective amount of atezolizumab is a dose of about 200 mg every three weeks (e.g., 200 mg ⁇ 10 mg, e.g., 200 ⁇ 6 mg, e.g., 200 ⁇ 5 mg, e.g., 200 ⁇ 3 mg, e.g., 200 ⁇ 1 mg, e.g., 200 ⁇ 0.5 mg, e.g., 200 mg every three weeks).
  • the effective amount of atezolizumab is a dose of about 200 mg every three weeks (e.g., 200 mg ⁇ 10 mg, e.g., 200 ⁇ 6 mg, e.g., 200 ⁇ 5 mg, e.g., 200 ⁇ 3 mg, e.g., 200 ⁇ 1 mg, e.g., 200 ⁇ 0.5 mg, e.g., 200 mg every three weeks).
  • the effective amount of atezolizumab is a dose of between 10 mg and 800 mg (e.g., between 10 mg and 800 mg, e.g., between 20 mg and 700 mg, e.g., between 50 mg and 600 mg, e.g., between 75 mg and 500 mg, e.g., between 100 mg and 400 mg, e.g., between 100 mg and 300 mg, e.g., between 125 mg and 275 mg, e.g., between 150 mg and 250 mg, e.g., between 175 mg and 225 mg, e.g., between 190 mg and 210 mg, e.g., 200 mg ⁇ 10 mg, e.g., 200 mg ⁇ 7.5 mg, e.g., 200 mg ⁇ 5 mg, e.g., 200 ⁇ 2.5 mg, e.g., 200 ⁇ 1.0 mg, e.g., 200 ⁇ 0.5 mg, e.g., 200 mg) every three weeks (Q3W
  • the effective amount of atezolizumab is a dose of 200 mg every three weeks (e.g., 200 mg ⁇ 10 mg, e.g., 200 ⁇ 6 mg, e.g., 200 ⁇ 5 mg, e.g., 200 ⁇ 3 mg, e.g., 200 ⁇ 1 mg, e.g., 200 ⁇ 0.5 mg, e.g., 200 mg every three weeks).
  • the effective amount of atezolizumab is a dose of 200 mg every three weeks (e.g., 200 mg ⁇ 10 mg, e.g., 200 ⁇ 6 mg, e.g., 200 ⁇ 5 mg, e.g., 200 ⁇ 3 mg, e.g., 200 ⁇ 1 mg, e.g., 200 ⁇ 0.5 mg, e.g., 200 mg every three weeks).
  • the effective amount of atezolizumab is a dose of about 200 mg every three weeks.
  • the effective amount of atezolizumab is a dose of 200 mg every three weeks.
  • the effective amount of atezolizumab is a dose of between about 80 mg to about 3000 mg (e.g., between about 80-200 mg, between about 200-400 mg, between about 400-600 mg, between about 600-800 mg, between about 800-1000 mg, between about 1000-1200 mg, between about 1200-1400 mg, between about 1400-1600 mg, between about 1600-1800 mg, between about 1800-2000 mg, between about 2200-2400 mg, between about 2400-2600 mg, between about 2600-2800 mg, or between about 2800-3000 mg, e.g., between about 100 mg and about 3000 mg, e.g., between about 200 mg and about 2900 mg, e.g., between about 500 mg to about 2800 mg, e.g., between about 600 mg to about 2700 mg, e.g., between about 650 mg to about 2600 mg, e.g., between about 700 mg to about 2500 mg, e.g., between about 1000 mg to about 2400 mg, e.g., between
  • the effective amount of atezolizumab is a dose of between 500 mg to 3000 mg (e.g., between 500 mg to 2800 mg, e.g., between 600 mg to 2700 mg, e.g., between 650 mg to 2600 mg, e.g., between 700 mg to 2500 mg, e.g., between 1000 mg to 2400 mg, e.g., between 1100 mg to 2300 mg, e.g., between 1200 mg to 2200 mg, e.g., PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO between 1300 mg to 2100 mg, e.g., between 1400 mg to 2000 mg, e.g., between 1500 mg to 1900 mg, e.g., between 1600 mg to 1800 mg, e.g., between 1620 mg to 1700 mg, e.g., between 1640 mg to 1690 mg, e.g., between 1660 mg to
  • the effective amount of atezolizumab is a dose of 1680 mg every four weeks (e.g., 1680 mg ⁇ 10 mg, e.g., 1680 ⁇ 6 mg, e.g., 1680 ⁇ 5 mg, e.g., 1680 ⁇ 3 mg, e.g., 1680 ⁇ 1 mg, e.g., 1680 ⁇ 0.5 mg, e.g., 1680 mg every four weeks).
  • the effective amount of atezolizumab is a dose of about 1680 mg every four weeks.
  • the effective amount of atezolizumab is a dose of 1680 mg every four weeks.
  • the effective amount of atezolizumab is a dose of between about 50 mg to about 2000 mg (e.g., between about 50-100 mg, between about 100-250 mg, between about 250-500 mg, between about 500-750 mg, between about 750-1000 mg, between about 1000-1250 mg, between about 1250-1500 mg, between about 1500-1750 mg, or between about 1750-2000 mg, e.g., between about 100 mg to about 1000 mg, between about 120 mg to about 900 mg, between about 150 mg to about 800 mg, between about 200 mg to about 700 mg, between about 250 mg to about 600 mg, between about 300 mg to about 500 mg, or between about 350 mg to about 450 mg, e.g., between about 50 mg to about 100 mg, between about 100 mg to about 200 mg, between about 200 mg to about 300 mg, between about 300 mg to about 400 mg, between about 400 mg to about 500 mg, between about 500 mg to about 600 mg, between about 600 mg to about 700 mg, between about 700 mg to about 800 mg, or between about 800 mg
  • the effective amount of atezolizumab is a dose of between 50 mg to 2000 mg (e.g., between 100 mg to 1000 mg, between 120 mg to 900 mg, between 150 mg to 800 mg, between 200 mg to 700 mg, between 250 mg to 600 mg, between 300 mg to 500 mg, or between 350 mg to 450 mg, e.g., between 50 mg to 100 mg, between 100 mg to 200 mg, between 200 mg to 300 mg, between 300 mg to 400 mg, between 400 mg to 500 mg, between 500 mg to 600 mg, between 600 mg to 700 mg, between 700 mg to 800 mg, or between 800 mg to 1000 mg, e.g., 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, or 500 mg, e.g., 400 mg) every six weeks (Q6W
  • the effective amount of the anti-PD-1 antagonist antibody is a dose of about 400 mg every six weeks (e.g., 400 mg ⁇ 10 mg, e.g., 400 ⁇ 6 mg, e.g., 400 ⁇ 5 mg, e.g., 400 ⁇ 3 mg, e.g., 400 ⁇ 1 mg, e.g., 400 ⁇ 0.5 mg, e.g., 400 mg every six weeks).
  • the dose of atezolizumab is a fixed dose.
  • the effective amount of atezolizumab is a dose of (e.g., a fixed dose) about 400 mg every six weeks.
  • the effective amount of atezolizumab is a dose (e.g., a fixed dose) of 400 mg every six weeks.
  • atezolizumab is administered intravenously.
  • atezolizumab is administered subcutaneously.
  • atezolizumab is PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO administered to the patient intravenously at a dose of about 840 mg every 2 weeks, about 1200 mg every 3 weeks, or about 1680 mg every 4 weeks.
  • Atezolizumab is administered to the patient intravenously at a dose of 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks.
  • a subject is administered a total of 1 to 20 doses of atezolizumab, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 doses.
  • the doses may be administered intravenously.
  • tiragolumab and/or atezolizumab may be administered in one or more dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 or more dosing cycles).
  • the dosing cycles of tiragolumab and/or atezolizumab continue until there is a loss of clinical benefit (e.g., confirmed disease progression, drug resistance, death, or unacceptable toxicity).
  • the length of each dosing cycle is about 7 to 42 days (e.g., 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 41 days, 42 days).
  • the length of each dosing cycle is about 14 days. In some instances, the length of each dosing cycle is about 21 days. In some instances, the length of each dosing cycle is about 28 days. In some instances, the length of each dosing cycle is about 42 days. In some instances, the length of each dosing cycle is about 7 days. In some instances, tiragolumab is administered on about Day 1 (e.g., Day 1 ⁇ 3 days) of each dosing cycle. In some instances, tiragolumab is administered on about Day 15 (e.g., Day 15 ⁇ 3 days) of each dosing cycle.
  • tiragolumab is administered on about Day 22 (e.g., Day 22 ⁇ 3 days) of each dosing cycle. In some instances, tiragolumab is administered on about Day 29 (e.g., Day 29 ⁇ 3 days) of each dosing cycle.
  • tiragolumab may be administered intravenously at a dose (e.g., a fixed dose) of about 600 mg PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO on Day 1 of each 21-day cycle (i.e., at a dose of about 600 mg every three weeks).
  • tiragolumab is administered intravenously at a dose (e.g., a fixed dose) of about 600 mg on Day 1 and Day 15 of each 28-day cycle (i.e., at a dose of about 420 mg every two weeks).
  • a dose e.g., a fixed dose
  • tiragolumab may be administered intravenously at a dose (e.g., a fixed dose) of about 600 mg on Day 1, Day 15, and Day 29 of each 42-day cycle (i.e., at a dose of about 420 mg every two weeks).
  • tiragolumab may be administered intravenously at a dose (e.g., a fixed dose) of about 600 mg on Day 1 and Day 22 of each 42-day cycle (i.e., at a dose of about 600 mg every three weeks).
  • atezolizumab is administered on about Day 1 (e.g., Day 1 ⁇ 3 days) of each dosing cycle.
  • atezolizumab is administered on about Day 15 (e.g., Day 15 ⁇ 3 days) of each dosing cycle.
  • atezolizumab may be administered intravenously at a dose of about 1200 mg on Day 1 of each 21-day cycle (i.e., at a dose of about 1200 mg every three weeks).
  • Atezolizumab may be administered intravenously at a dose of about 1200 mg on Day 1 and Day 15 of each 28-day cycle (i.e., at a dose of about 840 mg every two weeks).
  • tiragolumab is administered intravenously at a dose (e.g., a fixed dose) of 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of 600 mg every three weeks).
  • atezolizumab is administered on Day 1 (e.g., Day 1 ⁇ 3 days) of each dosing cycle.
  • Atezolizumab may be administered intravenously at a dose of 1200 mg on Day 1 of each 21-day cycle (i.e., at a dose of 1200 mg every three weeks).
  • tiragolumab and atezolizumab are administered on about Day 1 (e.g., Day 1 ⁇ 3 days) of each dosing cycle.
  • tiragolumab is administered intravenously at a dose of about 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of about 600 mg every three weeks) and atezolizumab is administered intravenously at a dose of about 1200 mg on Day 1 of each 21-day cycle (i.e., at a dose of about 1200 mg every three weeks).
  • tiragolumab is administered intravenously at a dose of 600 mg on Day 1 of each 21-day cycle (i.e., at a dose of 600 mg every three weeks) and atezolizumab is administered intravenously at a dose of 1200 mg on Day 1 of each 21-day cycle (i.e., at a dose of 1200 mg every three weeks).
  • tiragolumab is administered intravenously at a dose of about 420 mg on Day 1 of each 14-day cycle (i.e., at a dose of about 420 mg every two weeks) and atezolizumab is administered intravenously at a dose of about 840 mg on Day 1 of each 14-day cycle (i.e., at a dose of about 840 mg every two weeks).
  • tiragolumab is administered intravenously at a dose of 420 mg on Day 1 of each 14-day cycle (i.e., at a dose of about 420 mg every two weeks) and atezolizumab is administered intravenously at a dose of 840 mg on Day 1 of each 14-day cycle (i.e., at a dose of 840 mg every two weeks).
  • tiragolumab is administered intravenously at a dose of about 840 mg on Day 1 of each 28-day cycle (i.e., at a dose of about 840 mg every four weeks) and atezolizumab is administered intravenously at a dose of about 1680 mg on Day 1 of each 28-day cycle (i.e., at a dose of about 1680 mg every four weeks).
  • tiragolumab is administered intravenously at a dose of 840 mg on Day 1 of each 28-day cycle (i.e., at a dose of 840 mg every four weeks) and atezolizumab is administered intravenously at a dose of 1680 mg on Day 1 of each 28-day cycle (i.e., at a dose of 1680 mg every four weeks).
  • tiragolumab administered in a combination therapy may be reduced as compared to a standard dose of tiragolumab administered as a monotherapy.
  • the dose of tiragolumab administered in a combination therapy may be reduced as compared to a standard dose of tiragolumab administered as a monotherapy.
  • the dose of atezolizumab administered in a combination therapy e.g., a combination treatment with tiragolumab
  • the dose of atezolizumab administered in a combination therapy may be reduced as compared to a standard dose of atezolizumab administered as a monotherapy.
  • the dose of atezolizumab administered in a combination therapy may be reduced as compared to a standard dose of atezolizumab administered as a monotherapy.
  • tiragolumab Intravenous infusion and subcutaneous administration of tiragolumab and atezolizumab
  • tiragolumab is administered intravenously.
  • tiragolumab is administered subcutaneously.
  • atezolizumab is administered intravenously.
  • atezolizumab is administered subcutaneously.
  • tiragolumab is administered to the subject or population of subjects by intravenous infusion over about 60 ⁇ 15 minutes (e.g., about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, or about 75 minutes).
  • tiragolumab is administered to the subject or population of subjects by intravenous infusion over about 60 ⁇ 10 minutes (e.g., about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes).
  • 60 ⁇ 10 minutes e.g., about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, or about 70 minutes).
  • Atezolizumab is administered to the subject by intravenous infusion over about 60 ⁇ 15 minutes (e.g., about 45 minutes, about 46 minutes, about 47 minutes, about 48 minutes, about 49 minutes, about 50 minutes, about 51 minutes, about 52 minutes, about 53 minutes, about 54 minutes, about 55 minutes, about 56 minutes, about 57 minutes, about 58 minutes, about 59 minutes, about 60 minutes, about 61 minutes, about 62 minutes, about 63 minutes, about 64 minutes, about 65 minutes, about 66 minutes, about 67 minutes, about 68 minutes, about 69 minutes, about 70 minutes, about 71 minutes, about 72 minutes, about 73 minutes, about 74 minutes, or about 75 minutes).
  • tiragolumab is administered to the subject by intravenous infusion over about 30 ⁇ 10 minutes (e.g., about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes).
  • Atezolizumab is administered to the subject by intravenous infusion over about 30 ⁇ 10 minutes (e.g., about 20 minutes, about 21 minutes, about 22 minutes, about 23 minutes, about 24 minutes, about 25 minutes, about 26 minutes, about 27 minutes, about 28 minutes, about 29 minutes, about 30 minutes, about 31 minutes, about 32 minutes, about 33 minutes, about 34 minutes, about 35 minutes, about 36 minutes, about 37 minutes, about 38 minutes, about 39 minutes, or about 40 minutes).
  • Administration order and observation periods In some instances in which both tiragolumab and atezolizumab are administered to a subject or population of subjects, the tiragolumab is administered to the subject before the atezolizumab.
  • the method includes an intervening first observation period.
  • atezolizumab is administered to the subject.
  • tiragolumab is first administered to the subject and atezolizumab is administered to the subject following administration of tiragolumab.
  • the method further includes a second observation period following administration of atezolizumab.
  • the method includes both a first observation period following administration of tiragolumab and second observation period following administration of atezolizumab.
  • the first and second observation periods are each between about 30 minutes to about 60 minutes in length.
  • the method may include recording the subject’s vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 30 ⁇ 10 minutes after administration of tiragolumab or atezolizumab during the first or second observation periods.
  • the method may include recording the subject’s vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 15 ⁇ 10 minutes after administration of tiragolumab or atezolizumab during the first or second observation periods.
  • atezolizumab is administered to the subject or population of subjects before tiragolumab.
  • the method includes an intervening first observation period.
  • the method further includes a second observation period following administration of tiragolumab.
  • the method includes both a first observation period following administration of atezolizumab and a second observation period following administration of tiragolumab.
  • the first and second observation periods are each between about 30 minutes to about 60 minutes in length.
  • the method may include recording the subject’s vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 30 ⁇ 10 minutes after administration of atezolizumab or tiragolumab during the first or second observation periods.
  • the method may include recording the subject’s vital signs (e.g., pulse rate, respiratory rate, blood pressure, and temperature) at about 15 ⁇ 10 minutes after administration of atezolizumab or tiragolumab during the first or second observation periods.
  • a dose of an effective amount of tiragolumab is administered with a dose of atezolizumab in a combination therapy (e.g., a combination treatment of tiragolumab with atezolizumab), e.g., for treatment of a subject having a NSCLC.
  • a combination therapy e.g., a combination treatment of tiragolumab with atezolizumab
  • tiragolumab is administered every two weeks as described in Section III(D)(i) herein and atezolizumab is administered every two weeks as described in Section III(D)(ii) herein.
  • tiragolumab is administered every two weeks as described in Section III(D)(i) herein and atezolizumab is administered every three weeks as described in Section III(D)(ii) herein. In some instances, tiragolumab is administered every two weeks as described in Section III(D)(i) herein and atezolizumab is administered every four weeks as described in Section III(D)(ii) herein. In some instances, tiragolumab is administered every two weeks as described in Section III(D)(i) herein and atezolizumab is administered every six weeks as described in Section III(D)(ii) herein.
  • tiragolumab is administered every three weeks as described in Section III(D)(i) herein and atezolizumab is administered every two weeks as described in Section III(D)(ii) herein. In some instances, tiragolumab is administered every three weeks as described in Section III(D)(i) herein and atezolizumab is administered every three weeks as described in Section III(D)(ii) herein. In some instances, tiragolumab is administered every three weeks as described in Section III(D)(i) herein and atezolizumab is administered every four weeks as described in Section III(D)(ii) herein.
  • tiragolumab is administered every three weeks as described in Section III(D)(i) herein and atezolizumab is administered every six weeks as described in Section III(D)(ii) herein. In some instances, tiragolumab is administered every four weeks as described in Section III(D)(i) herein and atezolizumab is administered every two weeks as described in Section III(D)(ii) herein. In some instances, tiragolumab is administered every four weeks as described in Section III(D)(i) herein and atezolizumab is administered every three weeks as described in Section III(D)(ii).
  • tiragolumab is administered every four weeks as described in Section III(D)(i) herein and atezolizumab is administered every four weeks as described in Section III(D)(ii) herein. In some instances, tiragolumab is administered every four weeks as described in Section III(D)(i) herein and atezolizumab is administered every six weeks as described in Section III(D)(ii) herein. In some instances, tiragolumab is administered every two, three, or four weeks as described in Section III(D)(i) herein and atezolizumab is administered every two, three, four, or six weeks as described in Section III(D)(ii) herein.
  • the dose of tiragolumab is a dose of about 600 mg every three weeks. In some instances, the dose of tiragolumab is a dose of 600 mg every three weeks. In some instances, tiragolumab is administered (e.g., every three weeks) in a tiered dosing regimen (e.g., dosing based on body weight (BW) or body surface area (BSA) of a subject) and atezolizumab is administered at a dose from about 0.01 mg/kg to about 50 mg/kg (e.g., about 15 mg/kg) up to 1200 mg, e.g., every three weeks.
  • a tiered dosing regimen e.g., dosing based on body weight (BW) or body surface area (BSA) of a subject
  • atezolizumab is administered at a dose from about 0.01 mg/kg to about 50 mg/kg (e.g., about 15 mg/kg) up to 1200 mg, e.g., every three
  • tiragolumab is administered (e.g., every three weeks) in a tiered dosing regimen (e.g., dosing based on body weight (BW) or body surface area (BSA) of a subject) and atezolizumab is PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO administered at a dose from 0.01 mg/kg to 50 mg/kg (e.g., 15 mg/kg) up to 1200 mg, e.g., every three weeks.
  • a tiered dosing regimen e.g., dosing based on body weight (BW) or body surface area (BSA) of a subject
  • atezolizumab is PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO administered at a dose from 0.01 mg/kg to 50 mg/kg (e.g., 15 mg/kg) up to 1200 mg
  • Such dosing regimens can be utilized in treatments for subjects having relatively low body weight (e.g., 40 kg or less (e.g., from 5 kg to 40 kg, from 15 kg to 40 kg, or from 5 kg to 15 kg)) and have been developed through biosimulation studies based on extrapolations of pharmacokinetic parameters estimated from adult data.
  • the dose of tiragolumab is a tiered dose based on a subject’s body weight (e.g., body weight (BW) > 40 kg: 600 mg, BW > 15 kg and ⁇ 40 kg: 400 mg, and BW ⁇ 15 kg: 300 mg).
  • the dose of atezolizumab is a dose based on a subject’s body weight (e.g., 15 mg/kg). In some instances, the dose of atezolizumab is a dose based on a subject’s body surface area (e.g., body surface area (BSA) > 1.25 m 2 : 600 mg, BSA > 0.75 m 2 and ⁇ 1.25 m 2 : 450 mg, BSA > 0.5 m 2 and ⁇ 0.75 m 2 : 350 mg, and BSA ⁇ 0.5 m 2 : 300 mg).
  • body surface area e.g., body surface area (BSA) > 1.25 m 2 : 600 mg
  • BSA body surface area
  • BSA body surface area
  • BSA body surface area
  • the dose (e.g., about 600 mg) of tiragolumab is administered in combination with a dose of atezolizumab based on a subject’s body weight (e.g., 15 mg/kg) every three weeks.
  • the tiered dose e.g., body weight (BW) > 40 kg: 600 mg, BW > 15 kg and ⁇ 40 kg: 400 mg, and BW ⁇ 15 kg: 300 mg
  • BW body weight
  • the tiered dose e.g., body weight (BW) > 40 kg: 600 mg, BW > 15 kg and ⁇ 40 kg: 400 mg, and BW ⁇ 15 kg: 300 mg
  • a dose of atezolizumab based on a subject’s body surface area e.g., BSA > 1.25 m 2 : 600 mg, BSA > 0.75 m 2 and ⁇ 1.25 m 2 : 450 mg, BSA > 0.5 m 2 and ⁇ 0.75 m 2 : 350 mg, and BSA ⁇ 0.5 m 2 : 300 mg
  • atezolizumab is administered at a maximum dose of 1200 mg every three weeks.
  • the combination therapy is administered with one or more chemotherapeutic agents (e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or a non-platinum-based chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine)).
  • chemotherapeutic agents e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or a non-platinum-based chemotherapeutic agent (e.g., an antimetabolite (e.g., pemetrexed or gemcitabine)).
  • chemotherapeutic agents e.g., a platinum-based chemotherapeutic agent (e.g., carboplatin or cisplatin) and/or a non-platinum-based chemotherapeutic agent (e.g., an antimetabolite
  • the effective amount of tiragolumab to treat a subject having a cancer is a tiered dose based on a subject’s body weight, wherein the subject has a body weight of (a) less than or equal to 15 kg, and tiragolumab is administered at a dose of between about 10 mg to about 1000 mg every three weeks (e.g., about 300 mg every three weeks); (b) greater than 15 kg and less than or equal to 40 kg, and tiragolumab is administered at a dose of between about 10 mg to about 1000 mg every three weeks (e.g., about 400 mg every three weeks); or (c) greater than 40 kg, and tiragolumab is administered at a dose of between about 30 mg to about 1200 mg every three weeks (e.g., about 600 mg every three weeks).
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body weight, wherein the subject has a body weight of (a) less than or equal to 15 kg, and tiragolumab is administered at a dose of between about 250 mg to about 350 mg every three weeks (e.g., about 300 mg every three weeks); (b) greater than 15 kg and less than or equal to 40 kg, and tiragolumab is administered at a dose of between about 350 mg to about 450 mg every three weeks (e.g., about 400 mg every three weeks); or (c) greater than 40 kg, and tiragolumab is administered at a dose of between about 550 mg to about 650 mg every three weeks (e.g., about 600 mg every three weeks).
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body weight, wherein the subject has a body weight of (a) less than or equal to 15 kg, and tiragolumab is administered at a dose of about 300 mg every three weeks; (b) greater than 15 kg and less than or equal to 40 kg, and PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO tiragolumab is administered at a dose of about 400 mg every three weeks; or (c) greater than 40 kg, and tiragolumab is administered at a dose of about 600 mg every three weeks.
  • a dose of between about 0.01 mg/kg to about 50 mg/kg of the subject’s body weight e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g., between about 0.1 mg/kg to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g., between about 2.5 mg/kg to about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between about 10 mg/kg to about 20 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 ⁇ 2 mg/kg, about 15 ⁇ 1 mg/kg, about 15 ⁇ 0.5 mg/kg, about 15 ⁇ 0.2 mg/kg, or about 15 ⁇ 0.1 mg/kg, e.g., about 15 mg/kg) of atezolizumab is administered in combination with a tiered dose based on a subject’
  • a subject with a body weight of less than or equal to 15 kg is administered a dose of between about 10 mg to about 1000 mg every three weeks (e.g., about 300 mg every three weeks) of tiragolumab and a dose of between about 0.01 mg/kg to about 50 mg/kg of the subject’s body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g., between about 0.1 mg/kg to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g., between about 2.5 mg/kg to about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between about 10 mg/kg to about 20 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 ⁇ 2 mg/kg, about 15 ⁇ 1 mg/kg, about 15 ⁇ 0.5 mg/kg, about 15
  • a subject with a body weight of greater than 15 kg and less than or equal to 40 kg is administered a dose of between about 10 mg to about 1000 mg every three weeks (e.g., about 400 mg every three weeks) of tiragolumab and a dose of between about 0.01 mg/kg to about 50 mg/kg of the subject’s body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g., between about 0.1 mg/kg to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g., between about 2.5 mg/kg to about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between about 10 mg/kg to about 20 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 ⁇ 2 mg/kg, about 15 ⁇ 1 mg/kg, about 15 ⁇ 0.5 mg/
  • a subject with a body weight of greater than 40 kg is administered a dose of between about 30 mg to about 1200 mg every three weeks (e.g., about 600 mg every three weeks) of tiragolumab and a dose of between about 0.01 mg/kg to about 50 mg/kg of the subject’s body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g., between about 0.1 mg/kg to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g., between about 2.5 mg/kg to about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between about 10 mg/kg to about 20 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 ⁇ 2 mg/kg, about 15 ⁇ 1 mg/kg, about 15 ⁇ 0.5 mg/kg, about 15 ⁇
  • the effective amount of tiragolumab to treat a subject having a cancer is a tiered dose based on a subject’s body weight, wherein the subject has a body weight of (a) less than or equal to 15 kg, and tiragolumab is administered at a dose of between 10 mg to 1000 mg every three weeks (e.g., 300 mg every three weeks); (b) greater than 15 kg and less than or equal to 40 kg, and tiragolumab is administered at a dose of between 10 mg to 1000 mg every three weeks (e.g., 400 mg every three weeks); or (c) greater than 40 kg, and tiragolumab is administered at a dose of between 30 mg to 1200 mg every three weeks (e.g., 600 mg every three weeks).
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body weight, wherein the subject has a body weight of (a) less than or equal to 15 kg, and tiragolumab is administered at a dose of between 250 mg to 350 mg every three weeks (e.g., 300 mg every three weeks); (b) greater than 15 kg and less than or equal to 40 kg, and tiragolumab is administered at a dose of between 350 mg to 450 mg every three weeks (e.g., 400 mg every three weeks); or (c) greater than 40 kg, and tiragolumab is administered at a dose of between 550 mg to 650 mg every three weeks (e.g., 600 mg every three weeks).
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body weight, wherein the subject has a body weight of (a) less than or equal to 15 kg, and tiragolumab is administered at a dose of 300 mg every three weeks; (b) greater than 15 kg and less than or equal to 40 kg, and tiragolumab is administered at a dose of 400 mg every three weeks; or (c) greater than 40 kg, and tiragolumab is administered at a dose of 600 mg every three weeks.
  • a dose of between 0.01 mg/kg to 50 mg/kg of the subject’s body weight e.g., between 0.01 mg/kg to 45 mg/kg, e.g., between 0.1 mg/kg to 40 mg/kg, e.g., between 1 mg/kg to 35 mg/kg, e.g., between 2.5 mg/kg to 30 mg/kg, e.g., between 5 mg/kg to 25 mg/kg, e.g., between 10 mg/kg to 20 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., 15 ⁇ 2 mg/kg, 15 ⁇ 1 mg/kg, 15 ⁇ 0.5 mg/kg, 15 ⁇ 0.2 mg/kg, or 15 ⁇ 0.1 mg/kg, e.g., 15 mg/kg) of atezolizumab is administered in combination with a tiered dose based on a subject’s body weight of tiragolumab, wherein the subject has a body weight of (
  • a subject with a body weight of less than or equal to 15 kg is administered a dose of between 10 mg to 1000 mg every three weeks (e.g., 300 mg every three weeks) of tiragolumab and a dose of between 0.01 mg/kg to 50 mg/kg of the subject’s body weight (e.g., between 0.01 mg/kg to 45 mg/kg, e.g., between 0.1 mg/kg to 40 mg/kg, e.g., between 1 mg/kg to 35 mg/kg, e.g., between 2.5 mg/kg to 30 mg/kg, e.g., between 5 mg/kg to 25 mg/kg, e.g., between 10 mg/kg to 20 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., 15 ⁇ 2 mg/kg, 15 ⁇ 1 mg/kg, 15 ⁇ 0.5 mg/kg, 15 ⁇ 0.2 mg/kg, or 15 ⁇ 0.1 mg/kg, e.g.,
  • a subject with a body weight of greater than 15 kg and less than or equal to 40 kg is administered a dose of between 10 mg to 1000 mg every three weeks (e.g., 400 mg every three weeks) of tiragolumab and a dose of between 0.01 mg/kg to 50 mg/kg of the subject’s body weight (e.g., between 0.01 mg/kg to 45 mg/kg, e.g., between 0.1 mg/kg to 40 mg/kg, e.g., between 1 mg/kg to 35 mg/kg, e.g., between 2.5 mg/kg to 30 mg/kg, e.g., between 5 mg/kg to 25 mg/kg, e.g., between 10 mg/kg PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO to 20 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., 15 ⁇ 2 mg/kg, 15 ⁇ 1 mg
  • a subject with a body weight of greater than 40 kg is administered a dose of between 30 mg to 1200 mg every three weeks (e.g., 600 mg every three weeks) of tiragolumab and a dose of between 0.01 mg/kg to 50 mg/kg of the subject’s body weight (e.g., between 0.01 mg/kg to 45 mg/kg, e.g., between 0.1 mg/kg to 40 mg/kg, e.g., between 1 mg/kg to 35 mg/kg, e.g., between 2.5 mg/kg to 30 mg/kg, e.g., between 5 mg/kg to 25 mg/kg, e.g., between 10 mg/kg to 20 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., 15 ⁇ 2 mg/kg, 15 ⁇ 1 mg/kg, 15 ⁇ 0.5 mg/kg, 15 ⁇ 0.2 mg/kg, or 15 ⁇ 0.1 mg/kg, e.g., 15 mg
  • the effective amount of tiragolumab to treat a subject having a cancer is a tiered dose based on a subject’s body surface area.
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body surface area, wherein the subject has a body surface area of (a) less than or equal to 0.5 m 2 , and tiragolumab is administered at a dose of between about 10 mg to about 1000 mg every three weeks (e.g., about 300 mg every three weeks); (b) greater than 0.5 m 2 and less than or equal to 0.75 m 2 , and tiragolumab is administered at a dose of between about 10 mg to about 1000 mg every three weeks (e.g., about 350 mg every three weeks); (c) greater than 0.75 m 2 and less than or equal to 1.25 m 2 , and tiragolumab is administered at a dose of between about 10 mg to about 1000 mg every three weeks (e.g., about 450
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body surface area, wherein the subject has a body surface area of (a) less than or equal to 0.5 m 2 , and tiragolumab is administered at a dose of between about 250 mg to about 350 mg every three weeks (e.g., about 300 mg every three weeks); (b) greater than 0.5 m 2 and less than or equal to 0.75 m 2 , and tiragolumab is administered at a dose of between about 300 mg to about 400 mg every three weeks (e.g., about 350 mg every three weeks); or (c) greater than 0.75 m 2 and less than or equal to 1.25 m 2 , and tiragolumab is administered at a dose of between about 400 mg to about 500 mg every three weeks (e.g., about 450 mg every three weeks); or (d) greater than 1.25 m 2 , and tiragolumab is administered at a dose of between about 550 mg to about
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body surface area, wherein the subject has a body surface area of (a) less than or equal to 0.5 m 2 , and tiragolumab is administered at a dose of about 300 mg every three weeks; (b) greater than 0.5 m 2 and less than or equal to 0.75 m 2 , and tiragolumab is administered at a dose of about 400 mg every three weeks; (c) greater than 0.75 m 2 and less than or equal to 1.25 m 2 , and tiragolumab is administered at a dose of 450 mg every three weeks; or (d) greater than 1.25 m 2 , and tiragolumab is administered at a dose of about 600 mg every three weeks.
  • a dose of between about 0.01 mg/kg to about 50 mg/kg of the subject’s body weight e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g., between about 0.1 mg/kg to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g., between about 2.5 mg/kg to about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between about 10 mg/kg to about 20 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 ⁇ 2 mg/kg, about 15 ⁇ 1 mg/kg, about 15 ⁇ PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO 0.5 mg/kg, about 15 ⁇ 0.2 mg/kg, or about 15 ⁇ 0.1 mg/kg, e.g
  • a subject with a body surface area of less than or equal to 0.5 m 2 is administered a dose of between about 10 mg to about 1000 mg every three weeks (e.g., about 300 mg every three weeks) of tiragolumab and a dose of between about 0.01 mg/kg to about 50 mg/kg of the subject’s body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g., between about 0.1 mg/kg to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g., between about 2.5 mg/kg to about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between about 10 mg/kg to about 20 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 ⁇ 2 mg/kg, about 15 ⁇ 1 mg/kg, about 15 ⁇ 0.5 mg/kg
  • a subject with a body surface area of greater than 0.5 m 2 and less than or equal to 0.75 m 2 is administered a dose of between about 10 mg to about 1000 mg every three weeks (e.g., about 350 mg every three weeks) of tiragolumab and a dose of between about 0.01 mg/kg to about 50 mg/kg of the subject’s body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g., between about 0.1 mg/kg to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g., between about 2.5 mg/kg to about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between about 10 mg/kg to about 20 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 ⁇ 2 mg/kg, about 15 ⁇ 1 mg/kg, about
  • a subject with a body surface area of greater than 0.75 m 2 and less than or equal to 1.25 m 2 is administered a dose of between about 10 mg to about 1000 mg every three weeks (e.g., about 450 mg every three weeks) of tiragolumab and a dose of between about 0.01 mg/kg to about 50 mg/kg of the subject’s body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g., between about 0.1 mg/kg to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g., between about 2.5 mg/kg to about 30 mg/kg, e.g., between about 5 mg/kg to about 25 mg/kg, e.g., between about 10 mg/kg to about 20 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.g., about 15 ⁇ 2 mg/kg, about 15 ⁇ 1 mg/kg,
  • a subject with a body surface area of greater than 1.25 m 2 is administered a dose of between about 30 mg to about 1200 mg every three weeks (e.g., about 600 mg every three weeks) of tiragolumab and a dose of between about 0.01 mg/kg to about 50 mg/kg of the subject’s body weight (e.g., between about 0.01 mg/kg to about 45 mg/kg, e.g., between about 0.1 mg/kg to about 40 mg/kg, e.g., between about 1 mg/kg to about 35 mg/kg, e.g., between about 2.5 mg/kg to about 30 mg/kg, e.g., between about PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO 5 mg/kg to about 25 mg/kg, e.g., between about 10 mg/kg to about 20 mg/kg, e.g., between about 12.5 mg/kg to about 15 mg/kg, e.
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body surface area, wherein the subject has a body surface area of (a) less than or equal to 0.5 m 2 , and tiragolumab is administered at a dose of between 10 mg to 1000 mg every three weeks (e.g., 300 mg every three weeks); (b) greater than 0.5 m 2 and less than or equal to 0.75 m 2 , and tiragolumab is administered at a dose of between 10 mg to 1000 mg every three weeks (e.g., 350 mg every three weeks); (c) greater than 0.75 m 2 and less than or equal to 1.25 m 2 , and tiragolumab is administered at a dose of between 10 mg to 1000 mg every three weeks (e.g., 450 mg every three weeks); or (d) greater than 1.25 m 2 , and tiragolumab is administered at a dose of between 30 mg to 1200 mg every three weeks (e.g., 600 mg
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body surface area, wherein the subject has a body surface area of (a) less than or equal to 0.5 m 2 , and tiragolumab is administered at a dose of between 250 mg to 350 mg every three weeks (e.g., 300 mg every three weeks); (b) greater than 0.5 m 2 and less than or equal to 0.75 m 2 , and tiragolumab is administered at a dose of between 300 mg to 400 mg every three weeks (e.g., 350 mg every three weeks); or (c) greater than 0.75 m 2 and less than or equal to 1.25 m 2 , and tiragolumab is administered at a dose of between 400 mg to 500 mg every three weeks (e.g., 450 mg every three weeks); or (d) greater than 1.25 m 2 , and tiragolumab is administered at a dose of between 550 mg to 650 mg every three weeks (e.g.,
  • the effective amount of tiragolumab is a tiered dose based on a subject’s body surface area, wherein the subject has a body surface area of (a) less than or equal to 0.5 m 2 , and tiragolumab is administered at a dose of 300 mg every three weeks; (b) greater than 0.5 m 2 and less than or equal to 0.75 m 2 , and tiragolumab is administered at a dose of 400 mg every three weeks; (c) greater than 0.75 m 2 and less than or equal to 1.25 m 2 , and tiragolumab is administered at a dose of 450 mg every three weeks; or (d) greater than 1.25 m 2 , and tiragolumab is administered at a dose of 600 mg every three weeks.
  • a dose of between 0.01 mg/kg to 50 mg/kg of the subject’s body weight e.g., between 0.01 mg/kg to 45 mg/kg, e.g., between 0.1 mg/kg to 40 mg/kg, e.g., between 1 mg/kg to 35 mg/kg, e.g., between 2.5 mg/kg to 30 mg/kg, e.g., between 5 mg/kg to 25 mg/kg, e.g., between 10 mg/kg to 20 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., 15 ⁇ 2 mg/kg, 15 ⁇ 1 mg/kg, 15 ⁇ 0.5 mg/kg, 15 ⁇ 0.2 mg/kg, or 15 ⁇ 0.1 mg/kg, e.g., 15 mg/kg) of atezolizumab is administered in combination with a tiered dose based on a subject’s body surface area of tiragolumab, wherein the subject has a body surface area
  • a subject with a body surface area of less than or equal to 0.5 m 2 is administered a dose of between 10 mg to 1000 mg PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO every three weeks (e.g., 300 mg every three weeks) of tiragolumab and a dose of between 0.01 mg/kg to 50 mg/kg of the subject’s body weight (e.g., between 0.01 mg/kg to 45 mg/kg, e.g., between 0.1 mg/kg to 40 mg/kg, e.g., between 1 mg/kg to 35 mg/kg, e.g., between 2.5 mg/kg to 30 mg/kg, e.g., between 5 mg/kg to 25 mg/kg, e.g., between 10 mg/kg to 20 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., 15 ⁇ 2 mg/kg, 15 ⁇ 1 mg/
  • a subject with a body surface area of greater than 0.5 m 2 and less than or equal to 0.75 m 2 is administered a dose of between 10 mg to 1000 mg every three weeks (e.g., 350 mg every three weeks) of tiragolumab and a dose of between 0.01 mg/kg to 50 mg/kg of the subject’s body weight (e.g., between 0.01 mg/kg to 45 mg/kg, e.g., between 0.1 mg/kg to 40 mg/kg, e.g., between 1 mg/kg to 35 mg/kg, e.g., between 2.5 mg/kg to 30 mg/kg, e.g., between 5 mg/kg to 25 mg/kg, e.g., between 10 mg/kg to 20 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., 15 ⁇ 2 mg/kg, 15 ⁇ 1 mg/kg, 15 ⁇ 0.5 mg/kg, 15 ⁇ 0.2 mg/kg, or 15 ⁇
  • a subject with a body surface area of greater than 0.75 m 2 and less than or equal to 1.25 m 2 is administered a dose of between 10 mg to 1000 mg every three weeks (e.g., 450 mg every three weeks) of tiragolumab and a dose of between 0.01 mg/kg to 50 mg/kg of the subject’s body weight (e.g., between 0.01 mg/kg to 45 mg/kg, e.g., between 0.1 mg/kg to 40 mg/kg, e.g., between 1 mg/kg to 35 mg/kg, e.g., between 2.5 mg/kg to 30 mg/kg, e.g., between 5 mg/kg to 25 mg/kg, e.g., between 10 mg/kg to 20 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., 15 ⁇ 2 mg/kg, 15 ⁇ 1 mg/kg, 15 ⁇ 0.5 mg/kg, 15 ⁇ 0.2 mg/kg, or 15
  • a subject with a body surface area of greater than 1.25 m 2 is administered a dose of between 30 mg to 1200 mg every three weeks (e.g., 600 mg every three weeks) of tiragolumab and a dose of between 0.01 mg/kg to 50 mg/kg of the subject’s body weight (e.g., between 0.01 mg/kg to 45 mg/kg, e.g., between 0.1 mg/kg to 40 mg/kg, e.g., between 1 mg/kg to 35 mg/kg, e.g., between 2.5 mg/kg to 30 mg/kg, e.g., between 5 mg/kg to 25 mg/kg, e.g., between 10 mg/kg to 20 mg/kg, e.g., between 12.5 mg/kg to 15 mg/kg, e.g., 15 ⁇ 2 mg/kg, 15 ⁇ 1 mg/kg, 15 ⁇ 0.5 mg/kg, 15 ⁇ 0.2 mg/kg, or 15 ⁇ 0.1 mg/kg, e.g
  • an article of manufacture or kit containing materials useful for the prognostic assessment and/or treatment of individuals is provided.
  • articles of manufacture or kits can be used to identify an individual having a NSCLC who may benefit from treatment with (a) atezolizumab or (b) atezolizumab and tiragolumab.
  • Such articles of manufacture or kits may include (a) reagents for determining the expression level of one or more genes and (b) instructions for using the reagents to identify an individual having a NSCLC who may benefit from a treatment comprising (a) atezolizumab or (b) atezolizumab and tiragolumab.
  • Any of the articles of manufacture or kits described may include a carrier means being compartmentalized to receive in close confinement one or more container means such as vials, tubes, and the like, each of the container means comprising one of the separate elements to be used in the method.
  • the kit may also have containers containing nucleotide(s) for amplification of the target nucleic acid sequence and/or a container comprising a reporter-means, such as an enzymatic, fluorescent, or radioisotope label.
  • the article of manufacture or kit includes the container described above and one or more other containers including materials desirable from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes, and package inserts with instructions for use.
  • a label may be present on the container to indicate that the composition is used for a specific application, and may also indicate directions for either in vivo or in vitro use, such as those described above.
  • the article of manufacture or kit may further include a container including a pharmaceutically-acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer’s solution, and dextrose solution.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer’s solution, and dextrose solution.
  • BWFI bacteriostatic water for injection
  • phosphate-buffered saline such as phosphate-buffered saline, Ringer’s solution
  • dextrose solution such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer’s solution,
  • the article of manufacture or kit includes a container, a label on said container, and a composition contained within said container, wherein the composition includes one or more polynucleotides that hybridize to a complement of a locus described herein under stringent conditions, and the label on said container indicates that the composition can be used to evaluate the presence of a gene listed herein (e.g., CCL5, CXCR3, CCR7, or CXCR6, or a member of any one of the Ccr7.2, Ccr7.3, Cxcr3, Ccl5.1, Ifit, Mitotic, Cytotox.2, and Cytotox.4 gene signatures) in a sample, and wherein the kit includes instructions for using the polynucleotide(s) for evaluating the presence of the gene RNA or DNA in a particular sample type.
  • a gene listed herein e.g., CCL5, CXCR3, CCR7, or CXCR6, or a member of any one of the Ccr7.2, Ccr7.3, C
  • the article of manufacture or kit can include, for example: (1) an oligonucleotide, e.g., a detectably labeled oligonucleotide, which hybridizes to a nucleic acid sequence encoding a protein or (2) a pair of primers useful for amplifying a nucleic acid molecule.
  • the article of manufacture or kit can also include, e.g., a buffering agent, a preservative, or a protein stabilizing agent.
  • the article of manufacture or kit can further include components necessary for detecting the detectable label (e.g., an enzyme or a substrate).
  • the article of manufacture or kit can further include components necessary for analyzing the sequence of a sample (e.g., a restriction enzyme or a buffer).
  • the article of manufacture or kit can also contain a control sample or a series of control samples that can be assayed and compared to the test sample.
  • Each component of the article of manufacture or kit can be enclosed within an individual container and all of the various containers can be within a single package, along with instructions for interpreting the results of the assays performed using the kit.
  • Clonotypically expanded effector-like CD8 + T cells are often found in tumors, normal adjacent tissue, and peripheral blood of patients with various types of cancer (Wu et al., Nature, 579: 274-278, 2020).
  • the presence of these peripherally expanded T cell clones likely correlates with an active anti- tumor immune response since patients bearing transcriptional signatures indicative of clonal expansion are associated with favorable progression-free survival when treated with the anti-PD-L1 monoclonal antibody (mAb) atezolizumab in various clinical trials (Wu et al., Nature, 579: 274-278, 2020).
  • T cells in the blood do not exhibit the features of exhausted T cells (Tex) and are not believed to be derived from tumor-infiltrating lymphocytes (TILs), suggesting that expansion may not reflect a reversal of intratumoral Tex exhaustion by PD-1 blockade (Scott et al., Nature, 571: 270-274, 2019; Khan et al., Nature, 571: 211- 218, 2019; Wherry et al., Nat Rev Immunol, 15: 486-499, 2015; Sade-Feldman et al., Cell, 175: 998- 1013.e1020, 2018).
  • DCs dendritic cells
  • dLN tumor draining lymph node
  • TLS tertiary lymphoid structures
  • intratumoral lymphoid aggregates Fluorin et al., JCI Insight, 3: e124507, 2018; Yost et al., Nat Med, 25: 1251-1259, 2019; Dammeijer et al., Cancer Cell, 38: 685-700, 2020; Oh et al., Nature Cancer, 1: 681-691, 2020).
  • T cells primed in the dLN acquire PD-1 expression and are subsequently detected as PD-1 expressing T cells after migrating to the tumor site (Dammeijer et al., Cancer Cell, 38: 685-700, 2020).
  • PD-1 expression thus appears to more accurately reflect T cell activation status rather than indicating the presence of exhaustion.
  • PD-1 is expressed on “stem cell-like memory (Tscm)” or “resource” PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO CD8 + T cells that are believed to be the primary targets of PD-1/PD-L1 blockade (Siddiqui et al., Immunity, 50: 195-211 e110, 2019).
  • Blocking PD-1 signaling thus may result in the differentiation of these progenitors into T cells with cytolytic effector activity against tumor cells, perhaps via a recently described transient population of T precursor exhausted cells (Tpex) (Huang et al., Cell, 185: 1-18, 2022; Dammeijer et al., Cancer Cell, 38: 685-700, 2020; Kallies et al., Nat Rev Immunol, 20: 128-136, 2020; Connolly et al., Sci Immunol, 6: eabg7836, 2021).
  • Tpex transient population of T precursor exhausted cells
  • TIGIT T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory domains
  • TIGIT and PD-1 expression are highly correlated (Johnston et al., Cancer Cell, 26: 923-937, 2014). Co-expression may also define distinct populations of Tscm cells, with those co-expressing TIGIT and PD-1 reflecting cells more likely to differentiate into dysfunctional exhausted CD8 + T cells as opposed to functional effector or memory cells.
  • TIGIT and PD-1 together regulate the function of CD226 (Banta et al., Immunity, 55: 512-526, 2022), whose signaling activates the PI3K/AKT pathway leading to inactivation of FOXO1, a widely expressed transcription factor with important roles in regulating T cell differentiation, including the effector and memory pathways (Luo et al., Cancer Biol, 50: 13-20, 2018; Du et al., Proc Natl Acad Sci U S A, 115: E11731-E11740, 2018; Hedrick et al., Nat Rev Immunol, 12: 649-661, 2012).
  • TIGIT blockade acts on T cells in lymphoid organs or in tumors.
  • the present study investigated whether the addition of TIGIT blockade to PD-1/PD-L1 blockade affected T cell function primarily in the dLN, as has been reported for PD-1/PD-L1 blockade alone, and how combination blockade impacted T cell function and differentiation. Trafficking of T cells from dLN to the tumor was found to be necessary to elicit the full effect of dual blockade.
  • Combination treatment requires trafficking of lymphocytes from draining lymph nodes to tumor
  • PD-1 and TIGIT regulate costimulatory signals in T cells suggests that both receptors act at the same steps and anatomical sites in T cell activation (Chiang et al., J Immunother Cancer, 10: e004711, 2022).
  • Treatment with anti-PD-L1 and/or anti-TIGIT did not affect total CD8 + T cell, CD4 + T cell, or regulatory T cell (Treg) numbers in dLN or tumor, either with or without FTY720 treatment (Fig.7C).
  • a gp70 tetramer was used to detect T cell receptors (TCRs) specific for gp70, a tumor- associated, immunodominant retroviral antigen expressed by CT26 cells (Huang et al., Proc Natl Acad Sci U S A, 93: 9730-9735, 1996).
  • anti-TIGIT significantly increased the fraction of gp70 + CD8 + T cells; anti-PD-L1 alone had little effect (Fig.1B, left panel and Fig.7D).
  • the effectiveness of FTY720 treatment was further confirmed as gp70 + CD8 + T cell numbers were significantly increased in blood with anti-TIGIT or combination treatment, but not in FTY720 treated animals (Fig.1B, middle panel and Fig.7D).
  • combination checkpoint blockade relied on the continuous recruitment of newly generated T cells or could be sustained once trafficked T cells that were previously reshaped by combination therapy in the dLN had infiltrated into the tumor.
  • FTY720 was injected either at the time of combination checkpoint blockade or 7 days later to arrest continued T cell recruitment to the tumor. Although early administration of FYT720 blocked combination efficacy, delaying the blockade of T cell trafficking until 7 days after combination treatment resulted in only slight impairment in anti-tumor efficacy (Fig.1D).
  • RNA sequencing Single-cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) sequencing (scTCR-seq) were performed on T cells isolated from tumor, dLN, and blood from 31 mice. Further, antibody-derived tag sequencing (ADT-seq) was conducted with tetramers against gp70 or control antigens and cellular indexing of transcriptomes and epitopes (CITE-seq) against a panel of 18 proteins. Gene expression profiles of a large dataset of 305,908 T cells yielded 22 distinct clusters (Fig.9A; top row, far left).
  • the Ccl5 clusters shared expression of a number of genes associated with the four Cytotox clusters.
  • CITE-seq analysis using protein expression of various surface markers corroborated the categorization by gene expression (Figs.10A and 10B).
  • FTY720 largely ablated these effects, as expected since the expanded Ccl5.2 cells in the blood likely originated in dLN.
  • Tumors had relatively large proportions of clonally expanded gp70- and gp70 + TILs, comprised of Ccl5, Cytotox, Ifng, and Ifit clusters (Figs.2C and 2D). These cells were observed in the control group and with FTY720 treatment, however, indicating that many of them were pre-existing in tumor and may expand and differentiate intratumorally.
  • Combination treatment showed larger proportions of Ccl5.2 cells that were tetramer gp70 + versus gp70-, reflecting their probable infiltration from blood. D.
  • Combination treatment focuses the TCR clonal diversity of tumor antigen-specific CD8+ T cells
  • ADT count as a measure of CD8 + T cell specificity for the gp70 tumor antigen
  • the phenotypes of T cells with high antigen binding matched those with high clonal expansion, predominantly the Ccl5 and Cytotox clusters (Figs.3A and 3B).
  • Each clone was characterized by its majority ADT barcode type, with gp70+ as an indicator of tumor reactivity and gp70– as non-tumor reactivity (or reactivity to some other tumor antigen).
  • Fig.12A the largest clones observed with combination treatment represent T cells that have expanded in dLN, trafficked into blood, and infiltrated the tumor (Fig.12A), with possible additional expansion subsequently in tumor.
  • Dual-expanded clones were either high-avidity tumor-reactive or low-avidity non-tumor reactive types (Fig.3E).
  • Fig.3E both anti-PD-L1 and anti-TIGIT single-agent treatments expanded several high- avidity tumor-specific clones, these expanded in either dLN or tumor but not both, and were not highly expanded in blood.
  • Combination treatment both with and without FTY720 treatment, showed a greater tendency than other treatments for Ccl5.2 phenotypes to co-occur with Ccl5.1 and Ifit phenotypes.
  • Recently, in vivo trafficking of T cells into and out of tumors has been elegantly visualized using photoactivation, revealing a relationship between CD8 + T cell phenotypes and their tumor residency, and the recirculation of stem-like TCF1 + T cells from tumor back to dLN (Li et al., J Exp Med, 219: e20210749, 2022).
  • the clonal trajectory analysis shows that the Ccl5.2 cluster is a key phenotype involved in both the expansion and trafficking induced by the combination of anti-TIGIT and anti-PD-L1.
  • F. CD226 involvement in tumor-specific CD8+ T cell differentiation in dLN To validate the transcriptomic analyses highlighting the prominence of the Ccl5.2 and Cytotox.4 clusters, tumor-specific CD8 + T cells were immunophenotyped, focusing on markers associated with Tscm/Tpex/transitory states and exhaustion.
  • CD226 signaling can lead to reduced FOXO1 expression, allowing CD226 to impact CD8 + T cell differentiation decisions (Du et al., Proc Natl Acad Sci U S A, 115: E11731-E11740, 2018).
  • tumor-specific gp70 + CD8 + T cells were segregated based on CD226 expression.
  • Anti-TIGIT alone or in combination with anti-PD-L1 increased the frequency of gp70 + CD8 + T cells expressing CD226 in both dLN and tumor, with FTY720 treatment having minimal impact (Figs.5A and 5H).
  • gp70 + CD8 + T cells expressing CD226 were significantly more proliferative, as measured using Ki67 as a marker, but this was observed only in dLN and not tumor (Figs.5B and 5I). Few CD226 + gp70 + CD8 + T cells in dLN were na ⁇ ve as compared to the CD226- fraction (Fig.5C), and combination treatment, but not either monotherapy, increased the frequency of CD226 + gp70 + CD8 + T cells with a Teff or Tem phenotype whereas no effects were observed in the CD226- population (Fig.5D).
  • the transcription factor Tox is a key regulator of the T cell exhaustion pathway (Scott et al., Nature, 571: 270-274, 2019; Seo et al., Proc Natl Acad Sci U S A, 116: 12410-12415, 2019).
  • Anti-CD226 mAb showed a trend towards impairing the ability of combination treatment to increase the frequency of TCF1 + Tim3 + tumor-specific CD8 + T cells in dLN, but not in the tumor, consistent with the observation that tumor antigen-specific CD8+ T cells acquired stem-like phenotypes in the tumor dLN (Prokhnevska et al., Immunity, 56: 107-124, 2023) (Fig.5l).
  • Anti-CD226 mAb ablated the reduction in Tox-expressing cells mediated by combination therapy in dLN that was also maintained in tumor (Fig.5M).
  • CD8 + T cell trafficking between dLN and tumor is strictly required for anti-tumor efficacy but only until sufficient tumor-specific CD8 + T cells have infiltrated the tumor, at which point additional trafficking is less important;
  • combination treatment drives expansion of tumor-specific CD8 + T cell clones in both the dLN and tumor;
  • dual-expanded clones have phenotypic characteristics of effector and memory cells derived from Tscm/Tpex cells that have reduced exhaustion programming likely reflecting the reduced induction of the Tox transcription factor;
  • combination treatment focuses dual-expanded clones towards a limited, but largely tumor antigen-specific, TCR repertoire; and (5) modification of the tumor-specific CD8 + T cell profile is associated with CD226 expression.
  • the study shows how checkpoint blockade shapes the differentiation decisions of tumor-specific CD8 + T cells to elicit better and more productive anti-tumor responses.
  • the study shows that both anti-TIGIT and anti-PD-L1 were individually capable of expanding tumor-specific CD8 + T cells clones in dLN or tumors, indicative of activity at both sites, with anti-TIGIT somewhat surprisingly exerting a more significant effect than anti-PD-L1 alone.
  • only the combination blockade of both PD-L1 and TIGIT invoked coordinated dual expansion of a focused tumor- reactive CD8 + T cell clonal repertoire together with a less exhausted phenotype.
  • TIGIT and PD-1 coinhibitory pathways converge to inactivate CD226, providing a mechanistic rationale for dual blockade of these two checkpoint inhibitor receptors (Banta et al., Immunity, 55: 512-526, 2022).
  • Combination TIGIT/PD-1 blockade-enabled CD226 signaling would then contribute to the multitude of signals that determine CD8 + T cell differentiation fates following antigen-specific activation.
  • Tscm/Tpex cells have been proposed as targets for PD-1/PD-L1 targeted immunotherapies (Huang et al., Cell, 185: 1-18, 2022; Siddiqui et al., Immunity, 50: 195-211 e110, 2019; Kallies et al., Nat Rev Immunol, 20: 128-136, 2020; Connolly et al., Sci Immunol, 6: eabg7836, 2021), activation and differentiation of these cells may not be sufficient for driving robust efficacious activity in the cancer setting.
  • anti-PD-(L)1 may act on Tscm/Tpex cells and expand tumor-specific CD8 + Teff cells, these Teff cells are often transitory and eventually accumulate as exhausted T cells (Deak et al., Nature, 610: 161–172, 2022), a phenomenon that was observed in the CT26 tumor model with anti-PD-L1 monotherapy.
  • Anti-TIGIT monotherapy may also target Tscm/Tpex cells but exert a stronger effect on modification of differentiation programming, perhaps due to higher expression levels of TIGIT relative to PD-1 on Tscm/Tpex cells and its greater effect on CD226 activity.
  • TIGIT and PD-1 co-inhibitory molecules serve to direct the differentiation of activated T cells along the Tex pathway.
  • their combined blockade may favor T effector and memory cell differentiation, perhaps by ensuring optimal co-stimulatory signaling via CD28 and CD226.
  • CD226 signaling is an attractive mechanism to explain modulation of CD8 + T cell differentiation pathway decisions, through activation of AKT and subsequent degradation of FOXO1.
  • FOXO1 has been shown to be a transcriptional activator of PD-1, a requirement for sustainment of T cell memory and maintenance of stem-like properties, and a promoter of differentiation to terminal exhaustion (Staron et al., Immunity, 41: 802-814, 2014; Delpoux et al., J Exp Med, 215: 575-594, 2018; Delpoux et al., Cell Rep, 34: 108674, 2021; Utzschneider et al., Cell Rep, 22: 3454-3467, 2018).
  • CD226 is but one of many signals that are integrated by CD8 + T cells and determine the fate decisions following antigen-specific activation.
  • CD226 may play a critical role in the dLN to promote TCF1 + Tim3 + CD8 + T cells that are or become more competent effector cells, conferring protection from the exhaustion pathway. Once CD8 + T cells infiltrate tumors, however, CD226 may no longer be required to maintain this phenotype, suggestive of a CD226-mediated programming mechanism during early priming in dLN in response to tumor-specific antigens.
  • the effect of combination treatment on the CD226- fraction in tumor may be attribute to downregulation of CD226 following activation through tumor-expressed PVR (Braun et al., Immunity, 53: 805-823 e815, 2020; Weulersse et al., Immunity, 53: 824-839 e810, 2020).
  • blockade of the immune checkpoints TIGIT PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO and PD-1/PD-L1 drives qualitatively advantageous differentiation of tumor-specific CD8 + T cells in dLN that can then traffic to and infiltrate into tumors where they maintain their qualitatively better effector state.
  • CD8 + T cell clusters most profoundly affected by or responsive to the combination treatment of anti- TIGIT and anti-PD-L1 were those most highly expressing the chemokine receptors CXCR3 (Cxcr3, Ccl5.1 and Ccl5.2) and CXCR6 (Cxcr3, Ccl5.2, Cytotox.3 and Cytotox.4) raises implications as to whether the effects of combination treatment are acting solely on CD8 + T cells or if there may also be effects on CXCR3- or CXCR6-ligand producing antigen-presenting cells that also express PVR and PD-L1, the ligands for TIGIT and PD-1, respectively.
  • FcgR Fc gamma receptors
  • TIGIT and PD-1 blockade are comparable to recently described effects of combination therapy of anti-PD-L1 mAbs plus either wild-type IL-2 (Hashimoto et al., Nature, 610: 173– 181, 2022), which can result in systemic immune responses, or a version that aims to avoid toxicity by targeting PD-1 instead of activating CD25 (Deak et al., Nature, 610: 161–172, 2022).
  • Both IL-2 strategies altered the differentiation program of Tscm/Tpex cells to favor generation of highly functional Teff cells rather than exhausted cells.
  • IL-2 therapies such as aldesleukin (Rosenberg et al., J Immunol, 192: 5451-5458, 2014) or possibly even targeted or modified IL2 variants (Deak et al., Nature, 610: 161–172, 2022)
  • tiragolumab plus atezolizumab has a favorable safety profile and is well-tolerated (Cho et al., Lancet Oncol, 23: 781-792, 2022; Rodriguez-Abreu et al., J Clin Oncol, 38: 9503, 2020).
  • anti-TIGIT plus anti-PD-L1/PD-1 may represent an ideal cancer immunotherapy combination that could achieve the goal of generating desired tumor-specific clonotypes whose differentiation favors the production of memory and effector cells rather than Tex, and thus may be more effective for controlling tumor growth.
  • Example 2
  • Human CD8 + T cells were mapped onto the mouse reference CD8 + T cell UMAP (Fig.15A), with a median prediction accuracy above 60% for human CD8 + T cells assigned to the mouse Ccl5.2 cluster (Fig.15B).
  • the top 20 differentially expressed signature genes for each mouse CD8 + T cell cluster were identified and the average expression of orthologous human genes was examined (average expression referred to as the gene signature ‘score’) in CITYSCAPE samples (Table 4).
  • CD8 + T cell signature gene scores were compared in CITYSCAPE patients treated with T+A or P+A, clinically evaluated as being responders (complete response or partial response (CRPR)) or non-responders (stable disease or progressive disease (SDPD)), where baseline tumor bulk RNA-seq data was available.
  • Ccr7.3, Cxcr3, and Ccl5.1 gene signature scores were significantly higher in responders as compared to non-responders (Fig.6A).
  • CXCR3, CXCR6 and CCL5 were associated with improved OS for T+A, again outperforming CD8A (Fig.6D).
  • Example 3 Materials and Methods The following materials and methods were used in the experiments described in Examples 1 and 2. Mice BALB/c or C57BL/6 mice were purchased from the Charles River Laboratories. Cell Lines CT26 and EO771 cell lines were maintained at a dedicated internal cell line facility and tested to be mycoplasma-free.
  • CT26 or EO771 cells were cultured in RPMI 1640 media supplemented with 10% FBS and 100 U/mL penicillin and 100 mg/mL streptomycin, and grown in a 37 ⁇ C humidified, 5% CO2 incubator.
  • Syngeneic tumor studies CT26 tumor studies were performed by inoculating age-matched 6-8 week old BALB/c female mice with a sub-cutaneous injection of 0.1 x 10 6 CT26 cells in 100 ⁇ L Hank’s balanced solution (HBSS) and MATRIGEL® (BD Biosciences, San Jose, CA).
  • EO771 tumor studies were performed by inoculating age-matched 6-8 week old C57BL/6 female mice with an injection into the fifth mammary fat pad of 0.1 x 10 6 EO771 cells in 100 ⁇ L HBSS + MATRIGEL®.
  • tumors achieved a mean volume of 150-200 mm 3
  • animals were apportioned into treatment groups and treated with isotype control (anti-gp120 mIgG2a), 10 mg/kg; anti-PD-L1.mIgG2a LALAPG mAb (clone 6E11), 10 mg/kg followed by 5 mg/kg; anti- TIGIT.mIgG2a mAb (clone 10A7), 10 mg/kg; or TIGIT.mIgG2a.LALAPG, 10 mg/kg, and administered intravenously for the first dose and subsequently intraperitoneally.
  • doses were given three times a week for three weeks.
  • mice were euthanized at day 7 after initial treatment.
  • Tumors were dissociated into single cell suspensions by using GENTLEMACS TM Dissociator (Miltenyi Biotec) and enzymatically digested in a buffer containing collagenase D (2 mg/mL) and DNAse (40 U/mL, Roche).
  • Single cell suspensions of draining lymph nodes were obtained by mechanical dissociation through 40 ⁇ m cell strainers and performing red blood cell lysis as needed.
  • Blood was obtained by terminal cardiac puncture and collected in lavender MICROTAINER TM Blood Collection Tubes (BD Biosciences, 365974) and subjected to red blood cell lysis. Animals bearing tumors exceeding 2,000 mm 3 or showing ulceration were euthanized following approved protocols.
  • tumors and dLNs were processed into single cell suspensions as described elsewhere, and subjected to first tetramer staining, then surface markers and CITE-seq antibodies together. Processing of blood samples at day 0 before any treatment or at day 7 were first stained with hashed-tagged antibodies, then stained with surface markers. Cells were purified by fluorescence-activated cell sorting (FACS) on a Becton Dickinson FACSARIA TM Fusion cell sorter equipped with four lasers (405 nm, 488 nm, 561 nm and 638nm). A 70- ⁇ m nozzle running at 70 psi and 90 kHz was used as the setup for each sort session.
  • FACS fluorescence-activated cell sorting
  • FACSDIVA TM (v.8.0.1) and FlowJo (v.10) were used to collect and analyze the flow cytometry data.
  • FSC-A forward scatter
  • SSC-A side scatter
  • FSC-W/SSC-H FSC-W/FSC-H
  • FACS-W/FSC-H FACS-W/FSC-H
  • Antibodies and tetramers used for flow cytometry, cell sorting by FACS, or CITE-seq are shown in Tables 5 and 6.
  • pMHC monomers Single-cell RNA-seq and TCR V(D)J clonotype profiling Processing for single-cell expression (scRNA-seq) and T cell receptor V(D)J clonotypes (scTCR- seq) was done using the Chromium Single Cell 5’ Library and Gel Bead Kit (10x Genomics), following manufacturer’s instructions. Cell density and viability from each mouse tissue of FACS-sorted CD90 + T cells from tumor and blood, or CD90 + CD44 + T cells from draining lymph nodes, were determined by hemacytometer. Approximately 6,000-10,000 cells per sample were used for the reverse transcription mastermix.
  • TCR V(D)J enrichment was done per manufacturer’s user guide using Chromium Single Cell V(D) J Enrichment Kit, Human T cell (10x Genomics).
  • RNA-seq and V(D)J were prepared following the PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO manufacturer’s user guide (10x Genomics), then profiled using Bioanalyzer High Sensitivity DNA kit (Agilent Technologies) and quantified with Qubit (Thermo Fisher Scientific).
  • scRNA-seq libraries were sequenced in one lane of HiSeq4000 (Illumina).
  • scTCR V(D)J libraries were tagged with a sample barcode for multiplexed pooling with other libraries, sequenced in both lanes of a HiSeq2500 machine (Illumina) using Rapid Run mode, and then demultiplexed.
  • T cell receptor genes e.g., Trbv1 through Trbv31
  • Trbv T cell receptor genes
  • TCR sequence data from the filtered_contig_annotations.csv files were processed using a custom script that identified clones across multiple tissues in each mouse, based on identical sets of alpha and beta sequences.
  • ADT barcodes came from 12 distinct tetramers, of which 2 had gp70 antigens and the remaining 10 had a non-gp70 antigen (C28, UV, or C142).
  • a cell was assigned to an antigen based on its ADT barcode with the highest count, and cells were not assigned in cases of ties. Integration of single-cell expression data Analysis was performed in the statistical language R version 4.2.0 and with scripts written for Perl version 5.16.3.
  • centroids were used as reference gene signatures to assign each cell from the dataset, where genes with zero expression across an entire sample were excluded, gene expression for each cell was converted to log2(tpm+1), and assignment was performed by the SingleR package in R, using default parameters. Assignments between the two clustering schemes were cross- tabulated, and normalized by the total counts for each of the clusters.
  • Clone-based migration and differentiation trajectories To compute trajectories of T cells within clonal lineages, a trajectory method that utilizes clone information from scTCR-seq data was developed. First, a co-occurrence matrix was computed, with rows and columns corresponding to each phenotypic cluster in each tissue type.
  • Each clone was processed with n cells, where n > 1, by normalizing its distribution of cells across cluster/tissue groups as a vector x, whose sum is 1.
  • Each clone contributes to the co-occurrence matrix with its weighted outer product nxx T , where the outer product represents the frequency of any two cluster/tissue pairs occurring in the same clone, and weighting by n emphasizes data from larger clones.
  • the resulting co-occurrence matrix is PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO then analyzed for differentiation within each cluster by computing a minimum-spanning tree, where values from the co-occurrence matrix are considered as edges between the nodes represented on the rows and columns of the matrix.
  • T he second patient in the dataset was chosen at random as the integration reference.
  • transfer anchors were identified between the query human CD8 + T cell dataset and the mouse CD8 + T cell reference.
  • the MapQuery function in Seurat was used to transfer cell type labels, integrate embeddings, and to project the query data onto the reference UMAP.
  • Gene signature scores for CITYSCAPE The top 20 differentially expressed genes in each of the mouse CD8 + T cell clusters identified from scRNAseq were converted to their human orthologs using babelgene (version 22.9) in R (4.2.0). Mouse genes that did not have human orthologs or with human orthologs that were not present in the CITYSCAPE dataset were removed. The final curated table of signature genes used for analysis are in Table 4.
  • CITYSCAPE (NCT01903993) is a phase 2 trial investigating tiragolumab with atezolizumab compared to placebo with atezolizumab in patients with locally advanced or metastatic NSCLC (Cho et al., Lancet Oncol, 23: 781-792, 2022). Patients were treated until disease progression or loss of clinical benefit. Patient tumor samples were submitted for RNAseq and the average, log-normalized expression of the genes in Table 4 or selected genes as indicated in the text was used to define gene signature scores. Objective response was categorized according to RECIST (version 1.1).
  • KM survival curves and hazard ratios For Kaplan-Meier (KM) survival curves and hazard ratios, patients in the CITYSCAPE trial were separated by treatment group and further sub-divided by high or low expression of individual genes or gene signatures, where high or low is defined as at or above or below the global median expression, respectively, of that gene or gene signature score.
  • the survminer package version 0.4.9
  • survival package version 3.4-0
  • R version 4.2.0
  • a Cox proportional hazards regression model was fit on gene or gene signature score high or low data and the hazard ratio and 95% confidence interval for overall survival calculated and plotted for patients receiving tiragolumab with atezolizumab compared to patients receiving placebo with PATENT Attorney Docket No.: 50474-320WO2 Genentech Docket No.: P38318-WO atezolizumab.
  • KM survival curves for PFS and OS were generated for the phase 3 OAK study (NCT02008227) evaluating atezolizumab versus chemotherapy in PD-L1-positive previously treated patients with advanced or metastatic NSCLC.
  • Statistical Analysis Data were analyzed using GraphPad Prism software version 9 (GraphPad, San Diego, CA).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Analytical Chemistry (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • Wood Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Molecular Biology (AREA)
  • Hospice & Palliative Care (AREA)
  • Biophysics (AREA)
  • Oncology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

La présente invention concerne des méthodes pronostiques et thérapeutiques pour le traitement du cancer du poumon non à petites cellules (NSCLC) à l'aide de niveaux d'expression de gènes associés à des lymphocytes T CD8+. En particulier, l'invention concerne des procédés de sélection et de traitement de patients.
PCT/US2024/018472 2023-03-06 2024-03-05 Méthodes pronostiques et thérapeutiques contre le cancer du poumon non à petites cellules WO2024186790A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363488707P 2023-03-06 2023-03-06
US63/488,707 2023-03-06

Publications (1)

Publication Number Publication Date
WO2024186790A1 true WO2024186790A1 (fr) 2024-09-12

Family

ID=90482049

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/018472 WO2024186790A1 (fr) 2023-03-06 2024-03-05 Méthodes pronostiques et thérapeutiques contre le cancer du poumon non à petites cellules

Country Status (2)

Country Link
TW (1) TW202440631A (fr)
WO (1) WO2024186790A1 (fr)

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003072305A1 (fr) 2002-02-26 2003-09-04 Advanced Micro Devices, Inc. Procede et systeme destines a controler le polissage mecano-chimique de substrats par calcul du temps de surpolissage et/ou du temps de polissage d'une operation de polissage final
WO2004024072A2 (fr) 2002-09-11 2004-03-25 Genentech, Inc. Nouvelles compositions et methodes pour le traitement de maladies associees au systeme immunitaire
WO2004024068A2 (fr) 2002-09-11 2004-03-25 Genentech, Inc. Nouvelles composition et methodes servant au traitement de maladies associees au systeme immunitaire
WO2009126688A2 (fr) 2008-04-09 2009-10-15 Genentech, Inc. Compositions et procédés nouveaux pour le traitement de maladies de nature immunitaire
WO2015009856A2 (fr) 2013-07-16 2015-01-22 Genentech, Inc. Procédés de traitement du cancer à l'aide d'antagonistes se liant à l'axe pd-1 et inhibiteurs de mek
WO2016011264A1 (fr) 2014-07-16 2016-01-21 Genentech, Inc. Méthodes de traitement du cancer faisant appel à des inhibiteurs de tigit et à des agents anticancéreux
WO2016109546A2 (fr) 2014-12-30 2016-07-07 Genentech, Inc. Procédés et compositions de pronostic et de traitement du cancer
US20170088613A1 (en) 2015-09-25 2017-03-30 Genentech, Inc. Anti-tigit antibodies and methods of use
US20180030138A1 (en) 2015-05-12 2018-02-01 Genentech, Inc. Therapeutic and diagnostic methods for cancer
US20180037655A1 (en) 2015-05-29 2018-02-08 Genentech, Inc. Therapeutic and diagnostic methods for cancer
WO2018191660A1 (fr) * 2017-04-14 2018-10-18 Genentech, Inc. Méthodes diagnostiques et thérapeutiques afférentes au cancer
WO2019165434A1 (fr) 2018-02-26 2019-08-29 Genentech, Inc. Dosage pour traitement avec des anticorps antagonistes anti-tigit et anti-pd-l1
US20210301023A1 (en) * 2018-12-05 2021-09-30 Genentech, Inc. Diagnostic methods and compositions for cancer immunotherapy
WO2021252977A9 (fr) * 2020-06-12 2022-02-10 Genentech, Inc. Méthodes et compositions pour une immunothérapie anticancéreuse

Patent Citations (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003072305A1 (fr) 2002-02-26 2003-09-04 Advanced Micro Devices, Inc. Procede et systeme destines a controler le polissage mecano-chimique de substrats par calcul du temps de surpolissage et/ou du temps de polissage d'une operation de polissage final
WO2004024072A2 (fr) 2002-09-11 2004-03-25 Genentech, Inc. Nouvelles compositions et methodes pour le traitement de maladies associees au systeme immunitaire
WO2004024068A2 (fr) 2002-09-11 2004-03-25 Genentech, Inc. Nouvelles composition et methodes servant au traitement de maladies associees au systeme immunitaire
US8431350B2 (en) 2002-09-11 2013-04-30 Genentech, Inc. Composition and methods for the diagnosis of immune related diseases involving the PRO52254 polypeptide
US9499596B2 (en) 2008-04-09 2016-11-22 Genentech, Inc. Compositions and methods for the treatment of immune related diseases
WO2009126688A2 (fr) 2008-04-09 2009-10-15 Genentech, Inc. Compositions et procédés nouveaux pour le traitement de maladies de nature immunitaire
US20170145093A1 (en) 2008-04-09 2017-05-25 Genentech, Inc. Novel compositions and methods for the treatment of immune related diseases
US20170037127A1 (en) 2013-07-16 2017-02-09 Genentech, Inc. Methods of treating cancer using pd-1 axis binding antagonists and tigit inhibitors
US10626174B2 (en) 2013-07-16 2020-04-21 Genentech, Inc. Methods of treating cancer using PD-1 axis binding antagonists and TIGIT inhibitors
US20170044256A1 (en) 2013-07-16 2017-02-16 Genentech, Inc. Methods of treating cancer using pd-1 axis binding antagonists and tigit inhibitors
US10611836B2 (en) 2013-07-16 2020-04-07 Genentech, Inc. Methods of treating cancer using PD-1 axis binding antagonists and tigit inhibitors
US9873740B2 (en) 2013-07-16 2018-01-23 Genentech, Inc. Methods of treating cancer using PD-1 axis binding antagonists and TIGIT inhibitors
WO2015009856A2 (fr) 2013-07-16 2015-01-22 Genentech, Inc. Procédés de traitement du cancer à l'aide d'antagonistes se liant à l'axe pd-1 et inhibiteurs de mek
WO2016011264A1 (fr) 2014-07-16 2016-01-21 Genentech, Inc. Méthodes de traitement du cancer faisant appel à des inhibiteurs de tigit et à des agents anticancéreux
US20170260594A1 (en) 2014-12-30 2017-09-14 Genentech, Inc. Methods and compositions for prognosis and treatment of cancers
WO2016109546A2 (fr) 2014-12-30 2016-07-07 Genentech, Inc. Procédés et compositions de pronostic et de traitement du cancer
US20180030138A1 (en) 2015-05-12 2018-02-01 Genentech, Inc. Therapeutic and diagnostic methods for cancer
US20180037655A1 (en) 2015-05-29 2018-02-08 Genentech, Inc. Therapeutic and diagnostic methods for cancer
US20170088613A1 (en) 2015-09-25 2017-03-30 Genentech, Inc. Anti-tigit antibodies and methods of use
US10017572B2 (en) 2015-09-25 2018-07-10 Genentech, Inc. Anti-tigit antibodies and methods of use
US10047158B2 (en) 2015-09-25 2018-08-14 Genentech, Inc. Anti-TIGIT antibodies and methods of use
US20190119376A1 (en) 2015-09-25 2019-04-25 Genentech, Inc. Anti-tigit antibodies and methods of use
WO2017053748A2 (fr) 2015-09-25 2017-03-30 Genentech, Inc. Anticorps anti-tigit et méthodes d'utilisation
US20180186875A1 (en) 2015-09-25 2018-07-05 Genentech, Inc. Anti-tigit antibodies and methods of use
WO2018191660A1 (fr) * 2017-04-14 2018-10-18 Genentech, Inc. Méthodes diagnostiques et thérapeutiques afférentes au cancer
WO2019165434A1 (fr) 2018-02-26 2019-08-29 Genentech, Inc. Dosage pour traitement avec des anticorps antagonistes anti-tigit et anti-pd-l1
US20200399376A1 (en) * 2018-02-26 2020-12-24 Genentech, Inc. Dosing for treatment with anti-tigit and anti-pd-l1 antagonist antibodies
US20210301023A1 (en) * 2018-12-05 2021-09-30 Genentech, Inc. Diagnostic methods and compositions for cancer immunotherapy
WO2021252977A9 (fr) * 2020-06-12 2022-02-10 Genentech, Inc. Méthodes et compositions pour une immunothérapie anticancéreuse

Non-Patent Citations (68)

* Cited by examiner, † Cited by third party
Title
"Antibodies, A Laboratory Manual, and Animal Cell Culture", 1987
"Antibodies: A Practical Approach", 1988, IRL PRESS
"Cancer: Principles and Practice of Oncology", 1993, LIPPINCOTT COMPANY
"Cell and Tissue Culture: Laboratory Procedures", August 2008, J. WILEY AND SONS
"Current Protocols in Immunology", 1991
"Current Protocols In Molecular Biology", 1995, HARWOOD ACADEMIC PUBLISHERS
"Current Protocols in Molecular Biology", 2003
"Handbook of Experimental Immunology", 1994
"Introduction to Cell and Tissue Culture", 1998, ACADEMIC PRESS
"Oligonucleotide Synthesis", 1984
"UniProt", Database accession no. Q9NZQ7
"Using Antibodies: A Laboratory Manual", 1999, COLD SPRING HARBOR LABORATORY PRESS
"WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances", PROPOSED INN: LIST 117, vol. 31, no. 1380723-44-3, 9 June 2017 (2017-06-09)
"WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances", PROPOSED INN: LIST, vol. 31, no. 2, 9 June 2017 (2017-06-09)
BANTA ET AL., IMMUNITY, vol. 55, 2022, pages 512 - 526
BENDELL ET AL., CANCER RES, AACR ANNUAL MEETING 2020, 2020
CHIANG ET AL., J IMMUNOTHER CANCER, vol. 10, no. e004711, 2022, pages e004711
CHO ET AL., LANCET ONCOL, vol. 23, 2022, pages 781 - 792
CONNOLLY ET AL., SCIIMMUNOL, vol. 6, 2021, pages eabg7836
CONNOLLY ET AL.: "6", SCI IMMUNOL, vol. 6, 2021, pages eabg7836
DAMMEIJER ET AL., CANCER CELL, vol. 38, 2020, pages 685 - 700
DANGAJ ET AL., CANCER CELL, vol. 35, 2019, pages 885 - 900
DANIEL ET AL., NATIMMUNOL, vol. 23, 2022, pages 1614 - 1627
DANIEL ET AL.: "study", NAT IMMUNOL, vol. 23, 2022, pages 1614 - 1627
DELPOUX ET AL., CELL REP, vol. 34, 2021, pages 108674
DELPOUX ET AL., J EXP MED, vol. 215, 2018, pages 575 - 594
DU ET AL., PROC NATL ACAD SCI U S A, vol. 115, 2018, pages E11731 - E11740
DU ET AL., PROC NATL ACADSCIU S A, vol. 115, 2018, pages E11731 - E11740
DUCKWORTH ET AL., NAT IMMUNOL,, vol. 22, 2021, pages 434 - 448
FRANSEN ET AL., JCIINSIGHT, vol. 3, 2018, pages e124507
HASHIMOTO ET AL., NATURE, vol. 610, 2022, pages 161 - 172
HEDRICK ET AL., NAT REV IMMUNOL, vol. 12, 2012, pages 649 - 661
HUANG ET AL., CELL, vol. 185, 18 January 2022 (2022-01-18)
HUANG ET AL., CELL, vol. 185, 2022, pages 1 - 18
HUANG ET AL., PROC NATL ACAD SCI U SA, vol. 93, 1996, pages 9730 - 9735
JOHNSTON ET AL., CANCER CELL, vol. 26, 2014, pages 923 - 937
KALLIES ET AL., NAT REV IMMUNOL, vol. 20, 2020, pages 128 - 136
KIDMAN ET AL., FRONT IMMUNOL, vol. 11, 2020, pages 587014
LARROQUETTE MATHIEU ET AL: "Spatial transcriptomics of macrophage infiltration in non-small cell lung cancer reveals determinants of sensitivity and resistance to anti-PD1/PD-L1 antibodies", JOURNAL FOR IMMUNOTHERAPY OF CANCER, vol. 10, no. 5, 1 May 2022 (2022-05-01), pages e003890, XP093046993, Retrieved from the Internet <URL:https://jitc.bmj.com/content/jitc/10/5/e003890.full.pdf> DOI: 10.1136/jitc-2021-003890 *
LI ET AL., J EXP MED, vol. 219, 2022, pages e20210749
LUO ET AL., CANCER BIOL, vol. 50, 2018, pages 13 - 20
MAHNKE ET AL., EURJ IMMUNOL, vol. 43, 2013, pages 2797 - 2809
MEIER ET AL., NAT CANCER, vol. 3, 2022, pages 143 - 155
MILLER ET AL., NAT IMMUNOL, vol. 20, no. 3, 2019, pages 326 - 336
ODAJIU ET AL., FRONT INDOCRIN, vol. 11, 2021, pages 624122
OH ET AL., NATURE CANCER, vol. 1, 2020, pages 681 - 691
P. FINCH: "Immunobiology", 1997
PINSCHEWER ET AL., J IMMUNOL, vol. 164, 2000, pages 5761 - 5770
PROKHNEVSKA ET AL., IMMUNITY, vol. 56, 2023, pages 107 - 124
RAHIMI ET AL., ADV IMMUNOL, vol. 138, 2018, pages 71 - 98
RITTMEYER ET AL., LANCET, vol. 389, 2017, pages 255 - 265
RODRIGUEZ-ABREU ET AL., J CLIN ONCOL, vol. 38, 2020, pages 9503
ROSENBERG ET AL., J IMMUNOL, vol. 192, 2014, pages 5451 - 5458
SADE-FELDMAN ET AL., CELL, vol. 175, no. 998-1013, 2018, pages e1020
SAMBROOK ET AL.: "Molecular Cloning: A Laboratory Manual", 2001, COLD SPRING HARBOR LABORATORY PRESS
SCOTT ET AL., NATURE, vol. 571, 2019, pages 211 - 218
SEO ET AL., PROC NATL ACAD SCI U SA, vol. 116, 2019, pages 12410 - 12415
SIDDIQUI ET AL., IMMUNITY, vol. 50, no. 195-211, 2019, pages e110 - 1058
SIMONI ET AL., NATURE, vol. 557, 2018, pages 575 - 579
STARON ET AL., IMMUNITY, vol. 41, 2014, pages 802 - 814
TUMEH ET AL., NATURE, vol. 515, 2014, pages 568 - 571
UTZSCHNEIDER ET AL., CELL REP, vol. 22, 2018, pages 3454 - 3467
WEULERSSE ET AL., IMMUNITY, vol. 53, 2020, pages 824 - 839
WHERRY ET AL., NAT REV IMMUNOL, vol. 15, 2015, pages 486 - 499
WHO DRUG INFORMATION, vol. 28, no. 4, 2014, pages 488
WHO DRUG, INFORMATION, vol. 28, no. 4, 2014, pages 488
WU ET AL., NATURE, vol. 579, 2020, pages 274 - 278
YOST ET AL., NAT MED, vol. 25, 2019, pages 1251 - 1259

Also Published As

Publication number Publication date
TW202440631A (zh) 2024-10-16

Similar Documents

Publication Publication Date Title
JP7343565B2 (ja) 正規化バイオマーカースコアからがん治療を特定するためのシステム及び方法
JP7050702B2 (ja) Ｎｒｆ２及びその遺伝子の下流標的遺伝子の発現状態及び変異状態によるがんの診断及び治療方法
JP6901505B2 (ja) 全細胞がんワクチンおよびその選択のための方法
US20240018242A1 (en) Methods of treating cancer using lsd1 inhibitors in combination with immunotherapy
EP2874647B1 (fr) Procédé de diagnostic et de traitement de cancer metastasique
US20140274788A1 (en) Leukemia stem cell markers
KR20210100656A (ko) 암 면역요법을 위한 진단 방법 및 조성물
CN111148518A (zh) 使用cdk4/6抑制剂调控调节性t细胞和免疫应答的方法
CN105435228A (zh) 三氧化二砷的抗肿瘤新用途及抗肿瘤制剂
KR102338510B1 (ko) 항-her2 치료제에 대한 동반진단 마커 및 이의 용도
JP2022179694A (ja) Ｋｒａｓバリアントがん患者の免疫ベースの処置
US20240067970A1 (en) Methods to Quantify Rate of Clonal Expansion and Methods for Treating Clonal Hematopoiesis and Hematologic Malignancies
WO2020256868A9 (fr) Modulateurs du système immunitaire pour le traitement de la prémalignité du poumon squameux
WO2020146345A1 (fr) Méthodes de traitement du cancer à l&#39;aide d&#39;inhibiteurs de lsd1 et/ou d&#39;inhibiteurs de tgf/beta combinés à l&#39;immunothérapie
CN105189786A (zh) 用作治疗癌症的疗法的靶标的falz
TW201823471A (zh) 以視黃酸受體-α促效劑及抗CD38抗體治療病患之方法
CN117731781A (zh) Nat10促进剂在制备用于增强肝癌免疫治疗效果的增效剂中的应用
WO2024186790A1 (fr) Méthodes pronostiques et thérapeutiques contre le cancer du poumon non à petites cellules
CN117412987A (zh) 用于癌症治疗的cd274突变
US20220242955A1 (en) Targeting galectin-9 as a therapeutic strategy for t-cell exhaustion in t-cell acute lymphoblastic leukemia
US8883155B2 (en) Methods for treating hematopoietic malignancies
US20220142983A1 (en) Methods of treating cancer with farnesyltransferase inhibitors
US20180028601A1 (en) Methods and compositions for treating cancer
WO2024003241A1 (fr) Traitement pour des sujets résistants à l&#39;immuno-oncologie au moyen d&#39;un anticorps anti-pd-l1, d&#39;un composé antisens ciblant stat3 et d&#39;un inhibiteur de ctla-4
US20230250173A1 (en) Biomarkers for pd-1 axis binding antagonist therapy

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24714724

Country of ref document: EP

Kind code of ref document: A1