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WO2017136342A1 - Fulvestrant induisant la lyse cytotoxique à médiation immunitaire des cellules cancéreuses - Google Patents

Fulvestrant induisant la lyse cytotoxique à médiation immunitaire des cellules cancéreuses Download PDF

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Publication number
WO2017136342A1
WO2017136342A1 PCT/US2017/015829 US2017015829W WO2017136342A1 WO 2017136342 A1 WO2017136342 A1 WO 2017136342A1 US 2017015829 W US2017015829 W US 2017015829W WO 2017136342 A1 WO2017136342 A1 WO 2017136342A1
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cells
fulvestrant
vaccine
cancer
cancer cells
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PCT/US2017/015829
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English (en)
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Claudia M. Palena
Jeffrey Schlom
Marc Ferrer
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The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • EMT epithelial-mesenchymal transition
  • carcinoma cells undergoing EMT become resistant to cytotoxic treatments, including chemotherapy (Huang et al., Cell Death Dis., 4: e683 (2013; and Mitra et al., Oncotarget, 6: 10697-71 1 (2015)), radiation (Kurrey et al., Stem Cells, 27: 2059-68 (2009)), or small molecule targeted therapies (Thomson et al., Cancer Res., 65: 9455-62 (2005); and Byers et al., Clin. Cancer Res., 19: 279-90 (2013)).
  • EMT Interfering with, or reversing the process of EMT represents an attractive therapeutic modality against tumor dissemination and, perhaps more importantly, to minimize the occurrence of therapeutic resistance (Palena et el., Exp. Biol. Med. (Maywood), 236: 537-45 (201 1 ); Palena et al., Oncoimmunology, 3: e27220 (2014); and Davis et al., Trends Pharmacol. Sci., 35: 479-88 (2014)).
  • the invention provides a method of enhancing immune-mediated lysis of mesenchymal cancer cells comprising administering fulvestrant to the cancer cells, thereby enhancing immune-mediated lysis of cancer cells.
  • the invention provides a method of sensitizing mesenchymal cancer cells to chemotherapy or immune-mediated lysis comprising administering fulvestrant to the cancer cells, thereby sensitizing cancer cells to chemotherapy or immune-mediated lysis.
  • the invention also provides a method of treating lung cancer comprising administering a combination of fulvestrant and an immune-mediated therapy to a patient, thereby treating lung cancer.
  • Figs. 1A-E are images demonstrating H460-M clone exhibits resistance to cell death.
  • Fig. 1 A is a Western blot analysis of indicated proteins expressed by the H460-E and H460-M clones.
  • Figs. 1B-E are graphs showing susceptibility of H460-E vs. H460-M clone to (B) brachyury-specific CD8+ T cells, (C) NK effector cells, (D) recombinant TRAIL, and (E) cisplatin. Error bars indicate the standard error of the mean (SEM) of triplicate measurements. [* p ⁇ 0.05, ** p ⁇ 0.0 ⁇ , *** /? ⁇ 0.001 , **** / 0.0001].
  • Figs. 2A-C are graphs demonstrating that fulvestrant renders H460-M cells more sensitive to TRAIL-mediated lysis.
  • Fig. 2A is a graphical depiction of compounds having measurable activity in the qHTS assay. Large circles represent 53 hits with curves class of 4 when used with PBS, and curves classes -1 or -2 when used with TRAIL. The top three ranked compounds are fulvestrant, selegiline, and midazolam.
  • Fig. 2B are dose response curves of top compounds in combination with TRAIL vs. PBS.
  • Fig. 2C are graphs demonstratingTRAlL lysis of H460 cells treated for 48 hours with indicated concentrations of compounds prior to addition of 30 ng/mL TRAIL.
  • Figs. 3A-F are graphs demonstrating that fulvestrant renders mesenchymal cells more sensitive to immune-mediated lysis.
  • Fig. 3 A is a series of dose response curves of H460-E and H460-M cells treated with indicated doses of fulvestrant, 4-hydroxytamoxifen or DMSO to TRAIL-mediated lysis.
  • E Susceptibility to TRAIL-mediated lysis in cells pre-treated with fulvestrant vs. DMSO.
  • Figs. 4A-I are images demonstrating fulvestrant reverts immune-resistance of chemo-resistant HI 703 and H460 cells.
  • Fig 4A is a graph showing fold change in expression levels of indicated mRNA in chemo-resistant vs. control HI 703 cells.
  • Figs. 4B and 4C are raphs showing susceptibility of fulvestrant-treated cells to TRAIL (B) or (C) NK cells.
  • Fig. 4D are graphs showing sensitivity of the HI 703 pair to a combination of vinorelbine and cisplatin; tumor cells were left untreated (left panel) or treated with fulvestrant prior to exposure to chemotherapy.
  • Figs. 4A-I are images demonstrating fulvestrant reverts immune-resistance of chemo-resistant HI 703 and H460 cells.
  • Fig 4A is a graph showing fold change in expression levels of indicated mRNA in chemo-resistant v
  • FIGS. 4E and 4F are graphs showing fold-change in expression levels of indicated mRNA in chemo-resistant vs. control H460 cells.
  • FIG. 4G is an image showing immunohistochemical analysis of ESR1 expression in H460 tumor xenografts of mice treated with either HBSS or docetaxel.
  • Fig. 4H is a graph showing susceptibility of parental vs. chemo-resistant H460 treated with fulvestrant vs. DMSO to lysis by MUC1 - specific T cells.
  • Fig. 41 is a graph showing the effect of brachyury and ESR1 silencing on the susceptibility of indicated cells to TRAIL-mediated lysis. Error bars indicate the standard error of the mean (SEM) of triplicate measurements. [* p ⁇ 0.05, ** p ⁇ 0.0 ⁇ , *** juO.OOl].
  • Figs. 5A-G are graphs demonstrating that the estrogen receptor mediates resistance to immune attack.
  • H460 cells stably transfected with pCMV or a vector encoding the ESR1 gene were assessed for their sensitivity to NK-mediated lysis.
  • Figs. 5B and 5C single cell clones of H460 cells with High vs. Low ESR1 expression were evaluated for lysis by TRAIL (B) or (C) NK cells that were either untreated or pre-treated with CMA.
  • Fig. 5D demonstrates the expression of indicated mRNA, relative to GAPDH, in clonal H460 ESRl -High (gray bars) vs. ESRl-Low cells (black bars).
  • Figs. 5E and 5F show ESR1 mRNA (E) and ESR2 mRNA (F) in normal lung vs. lung adenocarcinoma tissues. Shaded areas correspond to the normal range of expression for each gene, calculated as the mean expression in normal lung tissues ( ⁇ two standard deviations).
  • Fig. 5G shows mRNA expression of the indicated genes in lung samples categorized as either ESR1 Low or High, based on the expression in normal lung tissues. Error bars indicate the standard deviation of the mean. [* p ⁇ 0.05, ** pO.01, *** pO.001 , **** pO.0001].
  • FIGs. 6A-F are images demonstrating that fulvestrant treatment reduces EMT markers and increases sensitivity of lung xenografts to doceta el.
  • Fig. 6A is a Western blot analysis of brachyury, fibronectin, and vimentin protein levels in H460 cells treated for six days with indicated concentrations of fulvestrant.
  • Fig. 6B is a schematic representation of the brachyury response element (AATTTCACACCTAGGTGTGAAATT; SEQ ID NO: 1).
  • Fig. 6C is a graph showing brachyury transcriptional activity in H460 cells treated for six days with indicated concentrations of fulvestrant.
  • Fig. 6A-F are images demonstrating that fulvestrant treatment reduces EMT markers and increases sensitivity of lung xenografts to doceta el.
  • Fig. 6A is a Western blot analysis of brachyury, fibronectin, and vimentin protein levels in H460
  • FIG. 6D is a graph showing brachyury promoter activity in H460 cells treated for three days with indicated concentrations of fulvestrant.
  • Fig. 6E are images showing estrogen receptor 1, brachyury, and fibronectin expression in H460 tumor xenografts five days after a single injection of either HBSS or fulvestrant.
  • Fig. 6F is a series of graphs showing tumor volume of H460 xenografts treated as indicated, with fulvestrant (250 mg/kg) given on days 4 and 11 and docetaxel (20 mg/kg) on days 7 and 10. Error bars indicate the standard error of the mean (SEM) of triplicate measurements. [* p ⁇ 0.05, ** p ⁇ 0M].
  • Fulvestrant is an FDA-approved, selective estrogen receptor antagonist used in the treatment of hormone receptor-positive breast cancer with well-known phamiacokinetics and pharmacological and toxicity profiles (Kuter et al., Breast Cancer Res. Treat., 133: 237-46 (2012) and Robertson et al., Clin. Pharmacokinet., 43: 529-38 (2004)).
  • the invention is predicated, at least in part, on the unexpected discovery that fulvestrant renders mesenchymal-like lung cancer cells significantly more susceptible to immune effector cells and chemotherapy.
  • a robust association between the acquisition of mesenchymal features by lung carcinoma cells and the expression of estrogen receptor 1 (Esrl , ER-alpha) and blockade of estrogen signaling via fulvestrant revert tumor phenotype while significantly augmenting tumor cell susceptibility to NK cells, tumor-reactive cytotoxic T cells, and chemotherapy.
  • the invention provides a method of enhancing immune-mediated lysis of mesenchymal cancer cells comprising administering fulvestrant to the cancer cells, thereby enhancing immune-mediated lysis of cancer cells.
  • the invention provides a method of sensitizing mesenchymal cancer cells to chemotherapy or immune-mediated lysis comprising administering fulvestrant to the cancer cells, thereby sensitizing mesenchymal cancer cells to chemotherapy or immune-mediated lysis.
  • the immune-mediated lysis is cytotoxic T-cell (CTL) mediated killing. In another embodiment, the immune-mediated lysis is natural killer (NK) cell mediated killing.
  • CTL cytotoxic T-cell
  • NK natural killer
  • fulvestrant treatment of mesenchymal-like carcinoma (e.g., lung carcinoma) cells increase immune-mediated cell death by repairing defective apoptotic mechanisms driven by the epithelial-mesenchymal transition (EMT).
  • EMT epithelial-mesenchymal transition
  • Treatment with fulvestrant reconstitutes sensitivity of tumor cells to chemotherapy and improved lysis by immune effector mechanisms including NK cells and antigen-specific T cells.
  • Non-limiting examples of specific types of cancer cells include cancer cells of the head and neck, eye, skin, mouth, throat, esophagus, chest, bone, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart or adrenals.
  • cancer cells include include cells from solid tumors, sarcoma, carcinomas, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelio sarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocar
  • the cancer cells are lung cancer cells (e.g., mesenchymal lung cancer cells).
  • the invention also provides a method of treating lung cancer comprising administering a combination of fulvestrant and an immune-mediated therapy to a patient, thereby treating lung cancer.
  • a combination of fulvestrant and an immune-mediated therapy can be used for the management of advanced lung cancer patients.
  • immunotherapy refers to the treatment of a disease by inducing, enhancing, or suppressing an immune response.
  • Immunotherapies designed to elicit or enhance an immune response are referred to as activation immunotherapies, while immunotherapies designed to suppress an immune response are referred to suppression immunotherapies.
  • Types of immunotherapies include, but are not limited to, checkpoint inhibitors, immunomodulators, cell-based
  • Immunomodulators can be recombinant, synthetic, or natural substances that include, but are not limited to, cytokines (e.g., TNF-a, IL-6, GM-CSF, IL-2, and interferons), co-stimulatory molecules (e.g., B7-1 and B7-2), chemokines (e.g., CCL3, CCL26, CXCL7), glucans, and oligodeoxynucleotides.
  • cytokines e.g., TNF-a, IL-6, GM-CSF, IL-2, and interferons
  • co-stimulatory molecules e.g., B7-1 and B7-2
  • chemokines e.g., CCL3, CCL26, CXCL7
  • Cell-based immunotherapies typically involve removal of immune cells (e.g., cytotoxic T-cells, natural killer cells, or antigen presenting cells (APCs)) from a subject, modification (e.g., activation) of immune cells, and return of the modified immune cells to the patient (e.g., adoptively transferred anti-tumor lymphocytes).
  • the cell-based immunotherapy desirably is Sipuleucel-T (PROVENGETM), which is an autologous active cellular immunotherapy used in the treatment of asymptomatic or minimally symptomatic CRPC (Plosker, G.L., Drugs, 77(1): 101-108 (201 1); and Kantoff et al, New Engl.
  • the inventive method comprises treating cancer cells with any suitable monoclonal antibody known in the art.
  • monoclonal antibodies include, for example, ipilumimab (YERVOYTM), which is a fully human antibody that binds to CTLA-4 and is indicated for the treatment of melanoma.
  • PD-1 programmed death receptor- 1
  • PD-Ll programmed death receptor- 1
  • PD-L2 programmed death receptor- 1 with its ligands PD-Ll and PD-L2
  • Antibodies that inhibit PD-1 signaling include, for example nivolumab (also known as BMS-936558 or MDX1106; see, e.g., ClinicalTrials.gov Identifier NCT00730639), sipuleucel-T CT-01 1 , pembrolizumab, atezolizumab, and MK-3575 (see, e.g., Patnaik et al., 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, Abstract # 2512). Monoclonal antibodies that specifically target prostate cancer are under development and also can be used in the invention (see, e.g., Jakobovits, A., Handb. Exp.
  • Monoclonal antibodies suitable for treatment of breast cancer include, for example, trastuzumab (HERCEPTINTM), pertuzumab (PERJETATM), and the antibody-drug conjugate ado-trastuzumab emtansine (KADCYLATM).
  • HERCEPTINTM trastuzumab
  • PERJETATM pertuzumab
  • KADCYLATM antibody-drug conjugate ado-trastuzumab emtansine
  • Cetuximab is an anti-EGFR antibody that is suitable for treatment of colorectal, non-small cell lung cancer, and squamous cell carcinoma of the head and neck.
  • Radiopharmaceuticals are radioactive drugs which are currently used to treat and diagnose a variety of diseases, including cancer.
  • radionuclides can be targeted to antibodies (i.e., radioimmunotherapy) to treat blood-derived cancers (Sharkey, R.M. and Goldenberg, D.M., Immunotherapy, 3(3): 349-70 (201 1)).
  • Several radioisotopes have been approved to treat cancer, including iodine-125, iodine-131 , and radium-223 (marketed as XOFIGOTM).
  • Radium-223 has been approved as a radiopharmaceutical to treat metastatic bone cancer and CRPC. In CRPC, radium-223 also has been shown to enhance the antitumor immune response.
  • Vaccines represent another strategy to prevent and treat cancer.
  • Many different cancer vaccine platforms are currently being evaluated in phase II and/or phase III clinical trials, including, for example, yeast-based vaccines, peptide-based vaccines, recombinant viral vectors, killed tumor cells, or protein-activated dendritic cells (see, e.g., Schlom, J., J. Natl. Cancer. Inst., 104: 599-613 (2012)). Any suitable vaccine can be used in the inventive method.
  • the vaccine is a yeast-based vaccine or a virus-based vaccine, such as a poxviral-based or adenoviral-based vaccine.
  • the vaccine can be the PSA/TRICOM vaccine (PROSTVACTM), which is a cancer vaccine composed of a series of poxviral vectors engineered to express PSA and a triad of human T-cell costimulatory molecules (see, e.g., Madan et al., Expert Opin. Investigational Drugs, 18(7): 1001-1011 (2009); and U.S.
  • the vaccine also can be a MUC-1/CEA vaccine (e.g., PANVAC), which is composed of a series of poxviral vectors (e.g., recombinant vaccinia and recombinant fowlpox) engineered to express MUC-1 and CEA and optionally human T-cell costimulatory molecules (e.g., TRICOM) (see, e.g., Madan et al, Expert Opin Biol Ther., 7(4): 543-54; International Patent Application Publications WO 2005/046622, WO 2005/046614, and WO 2015/061415); and U.S.
  • MUC-1/CEA vaccine e.g., PANVAC
  • poxviral vectors e.g., recombinant vaccinia and recombinant fowlpox
  • TRICOM optionally human T-cell costimulatory molecules
  • the cancer vaccine can comprise poxviral vectors (e.g., MVA and/or fowlpox) that have been genetically modified to express CEA and TRICOM (e.g., MVA/rF-CEA/TRICOM).
  • poxviral vectors e.g., MVA and/or fowlpox
  • the vaccine also can be a yeast MUC-1 immunotherapeutic, such as those described in, e.g., U.S. Patent Application Publication 2013/0315941 and
  • the vaccine can be a Brachyury vaccine, which comprises recombinant yeast or poxvirus that has been genetically modified to express the Brachyury transcription factor and optionally TRICOM (see, e.g., International Patent Application Publications WO 2014/043518 and WO 2014/043535; U.S. Patents 8,188,214 and 8,613,933; Heery et al., Cancer Immunol.
  • a Brachyury vaccine which comprises recombinant yeast or poxvirus that has been genetically modified to express the Brachyury transcription factor and optionally TRICOM (see, e.g., International Patent Application Publications WO 2014/043518 and WO 2014/043535; U.S. Patents 8,188,214 and 8,613,933; Heery et al., Cancer Immunol.
  • the vaccine comprises at least one (e.g., one two, three, four, five, or more) cancer antigen selected from the group consisting of CEA, MUC (e.g., MUC-1 , MUC-2, MUC-3, MUC-4, MUC-5AC, MUC-5B, MUC-6, MUC-7, MUC-11, and MUC-12), PSA, HER2, NY-ESO (e.g., NY-ESO-1), Brachyury, MAGE (e.g., MAGE-3, MAGE-6, and MAGE D), p53, GM- CSF, ras (e.g., k-ras and h-ras), gastrin, PANCIA, PANCIB, neoantigens, modified versions thereof (e.g., CEA(6D), and fragments thereof (e.g., mini-mucin).
  • MUC e.g., MUC-1 , MUC-2, MUC-3, MUC-4, MUC-5AC
  • the cancer cells can be in vivo or in vitro.
  • the term "in vivo” refers to a method that is conducted within living organisms in their normal, intact state, while an "in vitro ' " method is conducted using components of an organism that have been isolated from its usual biological context (e.g., isolating and culturing cells obtained from an organism).
  • the cancer cells are in vivo.
  • the cancer cells are lung cancer cells, preferably the lung cancer cells exist within a human male or female lung cancer.
  • the inventive methods induce a therapeutic effect in the cancer patient and treat the cancer (e.g., lung cancer).
  • the cancer cells can cancer cells (e.g., lung cancer cells) that have become resistant to other standard treatment regimens.
  • the cancer cells can be resistant to chemotherapy and/or radiation therapy.
  • the patient can be any suitable patient, such as a mammal (e.g., mouse, rat, guinea pig, hamster, rabbit, cat, dog, pig, goat, cow, horse, or primate (e.g., human)).
  • a mammal e.g., mouse, rat, guinea pig, hamster, rabbit, cat, dog, pig, goat, cow, horse, or primate (e.g., human)).
  • the terms “treatment,” “treating,” and the like refer to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect is therapeutic, i.e., the effect partially or completely cures a disease and/or adverse symptom attributable to the disease.
  • the inventive method comprises administering a "therapeutically effective amount" of fulvestrant, immunotherapy, and/or compositions thereof.
  • therapeutically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result.
  • the therapeutically effective amount may vary according to factors such as the disease state, age, and weight of the individual, and the ability of the fulvestrant, immunotherapy, and/or compositions thereof to elicit a desired response in the individual.
  • a combination of fulvestrant and immunotherapeutic agent can be administered sequentially or simultaneously.
  • fulvestrant is administered in combination with one or more (e.g., 2, 3, 4, or 5) immunotherapeutic agents (e.g., cancer vaccines).
  • the combination of a fulvestrant and immunotherapeutic agent can be administered with one or more (e.g., 2, 3, 4, or 5) additional therapeutic agents (e.g., chemotherapy, small molecule inhibitors (e.g., erlotinib, gefitinib, afatinib, osimertinib, bevacizumab, crizotinib, and ceritinib), endocrine deprivation therapy, androgen deprivation therapy (e.g., enzalutamide), a histone deacetylase (HDAC) inhibitor, and/or cabozantinib).
  • additional therapeutic agents e.g., chemotherapy, small molecule inhibitors (e.g., erlotinib, gefitinib, afatinib, osimertinib, bevacizumab, crizotinib, and ceritinib), endocrine deprivation therapy, androgen depri
  • ADT androgen deprivation therapy
  • Surgical approaches to ADT include surgical castration.
  • Pharmaceutical approaches to ADT include androgen inhibitors (antiandrogens) and chemical castration.
  • ADT also is referred to in the art as androgen suppression therapy.
  • Androgen inhibitors used in prostate cancer can be steroidal or non-steroidal (also referred to as "pure" antiandrogens).
  • Steroidal androgen inhibitors include, for example, e.g., megestrol (MEGACETM), cyproterone acetate, abiraterone, and abiraterone acetate (ZYTIGATM).
  • Nonsteroidal androgen inhibitors include, for example, bicalutamide (CASODEXTM), flutamide (EULEXINTM), nilutamide (ANANDRONTMand NILANDRONTM), and enzalutamide (XT AND ITM).
  • the androgen deprivation therapy is enzalutamide.
  • Enzalutamide (marketed as XT AND ITM by Medivation and Astellas and formally known as MDV3100) is an oral non-steroidal small molecule androgen receptor inhibitor that prolongs survival in men with metastatic castration resistant prostate cancer in whom the disease has progressed after chemotherapy. Preclinical studies also suggest that enzalutamide also inhibits breast cancer cell growth (see, e.g., Cochrane et al., Cancer Research, 72(24 Suppl): Abstract nr P2- 14-02 (2012)).
  • the androgen deprivation therapy is abiraterone, which is formulated as abiraterone acetate and marketed as ZYTIGATM by Janssen Biotech, Inc.
  • Abiraterone inhibits CYP17A1 , a rate-limiting enzyme in androgen biosynthesis. Inhibition of CYP17A1 subsequently blocks the production of androgen in all endocrine organs, including the testes, adrenal glands, and in prostate tumors (Harris et al., Nature Clinical Practice Urology, 6(2): 76-85(2009)).
  • abiraterone was shown to improve overall survival by 3.9 months compared to placebo (de Bono et al., New England ! Med., 3(54(21): 1995-2005(2011)). Abiraterone is indicated for use in combination with prednisone to treat CRPC.
  • endocrine deprivation therapy refers to a treatment for breast cancer in which the level of endocrine hormones, such as estrogen and/or testosterone, in a patient are reduced, typically by pharmaceutical or surgical methods (see, e.g., Angel opoulos et al, Endocr. Relat. Cancer, 11: 523-535 (2004); Dhingra, ., Invest. New Drugs, 17(3): 285-31 1 (1999); and Garay, J.P. and Park, B.H., Am. J. Cancer Res., 2(4): 434-445 (2012)).
  • Surgical approaches to endocrine deprivation include oophorectomy.
  • the endocrine deprivation therapy is an androgen inhibitor such as, for example, cyproterone acetate, abiraterone, abiraterone acetate (ZYTIGATM), or enzalutamide (XTANDITM).
  • the androgen inhibitor preferably is abiraterone or enzalutamide.
  • the endocrine deprivation therapy is an estrogen inhibitor, such as, for example, megestrol (MEGACETM), an aromatase inhibitor (e.g., anastrozole), a selective estrogen receptor down- regulator (SERD) (e.g., fulvestrant), a gonadotropin-releasing hormone (GnRH) analogue, or a selective estrogen receptor modulator (SERM) (e.g., tamoxifen or raloxifene).
  • MEGACETM megestrol
  • SESD selective estrogen receptor down- regulator
  • GnRH gonadotropin-releasing hormone
  • SERM selective estrogen receptor modulator
  • the estrogen inhibitor preferably is tamoxifen.
  • Tamoxifen is a selective estrogen receptor modulator (SERM) which is indicated for the treatment of metastatic breast cancer in women and men and ductal carcinoma in situ. Tamoxifen a nonsteroidal agent that binds to estrogen receptors (ER), inducing a
  • the invention includes a prime and boost protocol.
  • the protocol includes an initial "prime” with a composition comprising fulvestrant and optionally one or more immunotherapeutic agents (e.g., cancer vaccines) followed by one or preferably multiple (e.g., two, three, four, five, six, or more) "boosts" with a composition containing one or more immunotherapeutic agents (e.g., cancer vaccines) and optionally fulvestrant.
  • immunotherapeutic agents e.g., cancer vaccines
  • the protocol includes a prime with a composition comprising one or more immunotherapeutic agents (e.g., cancer vaccines) and optionally fulvestrant followed by one or multiple boosts with a composition comprising fulvestrant.
  • immunotherapeutic agents e.g., cancer vaccines
  • optionally fulvestrant followed by one or multiple boosts with a composition comprising fulvestrant.
  • fulvestrant When fulvestrant is administered with one or more immunotherapeutic agents (e.g., vaccines, such as cancer vaccines), the fulvestrant and one or more immunotherapeutic agents (e.g., cancer vaccines) can be coadministered to the mammal.
  • coadministering is meant administering one or more immunotherapeutic agents (e.g., cancer vaccines) and the fulvestrant sufficiently close in time such that the fulvestrant can enhance the effect of the one or more immunotherapeutic agents (e.g., cancer vaccines).
  • the fulvestrant can be administered first and the one or more immunotherapeutic agents (e.g., cancer vaccines) can be administered second, or vice versa.
  • the fulvestrant and the one or more immunotherapeutic agents e.g., cancer vaccines
  • fulvestrant and an anti-EGFR therapy are administered to a subject.
  • an anti-EGFR therapy e.g., erlotinib, gefitinib, afatinib, osimertinib, and/or cetuximab
  • erlotinib, gefitinib, afatinib, osimertinib, and/or cetuximab are administered to a subject.
  • the fulvestrant, an immunotherapeutic agent, and/or compositions thereof can be administered to a subject by various routes including, but not limited to, subcutaneous, intramuscular, intradermal, intraperitoneal, intravenous, and intratumoral. When multiple administrations are given, the administrations can be at one or more sites in a subject.
  • fulvestrant, an immunotherapeutic agent, and/or compositions thereof can be “prophylactic” or “therapeutic.”
  • the fulvestrant, an immunotherapeutic agent, and/or compositions thereof is provided in advance of tumor formation to allow the host's immune system to fight against a tumor that the host is susceptible of developing.
  • hosts with hereditary cancer susceptibility are a preferred group of patients treated with such prophylactic immunization.
  • the prophylactic administration of fulvestrant, an immunotherapeutic agent, and/or compositions thereof prevents, ameliorates, or delays cancer.
  • the fulvestrant, an immunotherapeutic agent, and/or compositions thereof is provided at or after the diagnosis of cancer.
  • the host has already been diagnosed with cancer (e.g., metastatic cancer)
  • the fulvestrant, an immunotherapeutic agent, and/or compositions thereof can be administered in conjunction with other therapeutic treatments such as chemotherapy or radiation.
  • compositions for oral, aerosol, parenteral (e.g., subcutaneous, intravenous, intraarterial, intramuscular, intradermal, interperitoneal, and intrathecal), rectal, and vaginal administration are merely exemplary and are in no way limiting.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid,
  • microcrystalline cellulose acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • Fulvestrant, a immunotherapeutic agent, and/or compositions thereof can be made into aerosol formulations to be administered via inhalation.
  • aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Fulvestrant, immunotherapeutic agent, and/or compositions thereof can be administered in aqueous and nonaqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Fulvestrant, immunotherapeutic agent, and/or compositions thereof can be administered in a
  • physiologically acceptable diluent in a pharmaceutical carrier such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, glycerol ketals, such as 2,2-dimethyl-l,3-dioxolane-4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.
  • Oils which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene-polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (3) mixtures thereof.
  • Suitable preservatives and buffers can be used in such formulations.
  • such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17.
  • HLB hydrophile-lipophile balance
  • the quantity of surfactant in such formulations ranges from about 5% to about 15% by weight.
  • Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
  • sterile liquid carrier for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.
  • Fulvestrant, an immunotherapeutic agent, and/or compositions thereof can be administered as an injectable formulation.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Pharmaceutics and Pharmacy Practice, J. B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986).
  • Topical formulations including those that are useful for transdermal drug release, are well known to those of skill in the art and are suitable in the context of the invention for application to skin.
  • the fulvestrant, immunotherapeutic agent, and/or compositions thereof can be administered as a suppository by mixing with a variety of bases, such as emulsifying bases or water-soluble bases.
  • bases such as emulsifying bases or water-soluble bases.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.
  • the fulvestrant, immunotherapeutic agent, and/or compositions thereof can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.
  • inclusion complexes such as cyclodextrin inclusion complexes, or liposomes.
  • Liposomes can serve to target fulvestrant, the immunotherapeutic agent, and/or compositions thereof to a particular tissue. Liposomes also can be used to increase the half-life of fulvestrant, the
  • the invention further provides a kit that contains fulvestrant and
  • the kit further provides containers, injection needles, and instmctions on how to use the kit.
  • H460 and HI 703 cells were originally purchased from the American Type Culture Collection (ATCC) and propagated as recommended. The cells lines were authenticated by short tandem repeat (STR) analysis (Bio-Synthesis Inc. or IDEXX BioResearch) in Jan 2013, May 2014 and Dec 2015. Two single cell-derived clonal populations of H460 cells, designated as H460-M and H460-E were expanded from the parental H460 cell line. Cells were not Chemoresistant H1703-Cis/Vin cells were generated by repeated (4-6 cycles) weekly exposure of H1703 cells to culture medium containing 500 ng/mL cisplatin (APP Pharmaceuticals) and 40 ng/mL vinorelbine (Tocris) for six hours. Chemoresistant H460- Cis/Vin cells were generated by continuous growth in the presence of 10 ng/mL cisplatin and 1 ng/mL vinorelbine.
  • STR short tandem repeat
  • NPC collection consisting of 2816 small molecule compounds, was assembled as described in Huang et al., Science Translational Medicine, 3:80psl 6 (201 1 ). Approximately 50% of compounds in the collection are approved for human or animal use by the United States Food and Drug Administration (FDA).
  • FDA United States Food and Drug Administration
  • H460-M cells were dispensed in two sets of 1536- well plates (Greiner Bio-One) at 1000 cells/well in 5 of phenol red-free RPMI-1640 medium supplemented with 5% FBS, using a Multidrop Combi Reagent dispenser and a small pin cassette (Thermo Scientific). After overnight incubation, 23 nL of compounds in DMSO were transferred using a Kalypsys pin tool. Plates were covered with stainless steel Kalypsys lids and placed at 37 ° C, with 5% CO 2 and 95% relative humidity.
  • each set of plates received 1 ah of PBS or recombinant TRAIL (30 ng/mL final concentration, Enzo Life Sciences, Farmingdale, NY, USA) dispensed with a Multidrop Combi Reagent dispenser and a small pin cassette.
  • Cell viability was assessed at four hours post-TRAIL addition (PBS for vehicle set) by dispensing 3 ⁇ . of CellTiter-Glo reagent (Promega, Madison, WI, USA) with a BioRAPTR® (Beckman Coulter, Indianapolis, IN, USA). Plates were incubated for 30 minutes at room temperature, spun at 1000 rpm and relative luciferase units (RLU) were quantified using a View Lux (PerkinElmer. Waltham, MA, USA).
  • the NPC library of compounds were transferred to columns 5-48 and controls were added in columns 1-4 of the 1536-well assay plate.
  • Columns 1 and 2 contained DMSO and PBS or TRAIL, respectively; columns 3 and 4 contained proteasome inhibitor bortezomib (10 ⁇ /L final concentration) and PBS or TRAIL, respectively.
  • CRC values of -1.1 , -1.2, -2.1 and -2.2 are considered highest quality hits; CRC values of -1.3, -1.4, -2.3, -2.4 and -3 are inconclusive hits; and CRC values of 4 are inactive compounds. Additional parameters obtained from qHTS and used for hit selection were the Maximum Response, which is the % activity at the maximum concentration of compound tested (46 ⁇ /L) and the AC 50 , which is obtained from the curve fitting obtained using the CRC algorithm.
  • the plasmids encoding the full-length human brachyury and ESR1 along with empty vectors were purchased from Origene Technologies (Rockville, MD, USA).
  • Brachyury and GAPDH promoter reporter plasmids were purchased from SwitchGear genomics. Brachyury promoter activity was normalized to GAPDH promoter activity. The protein expression laboratory, NCI-Frederick, produced the plasmid encoding the brachyury response element.
  • transfecting reagent were purchased from GE Dharmacon (Lafayette, CO, USA). Cells were transfected with 25 nmole/L siRNA constructs using the manufacture's recommended protocol. Assays were performed 72 hours post-transfection.
  • RNA isolation and real time PCR assays were performed as described in Hamilton et al. ⁇ Seminars in Oncology, 39: 358-66 (2012)) utilizing recommended probes (Life
  • Estrogen signaling qPCR array was purchased from SA Biosciences (Valencia CA, USA). Expression was normalized to glyceraldehyde-3- phosphate dehydrogenase (GAPDH). ESRl/2 expression in association with various markers of EMT in lung cancer was assessed using a TCGA dataset containing data from 490 lung adenocarcinomas and 58 histologically normal lung tissues (http://cancergenome.nih.gov/; downloaded April 2014). Data were analyzed utilizing the Nexus Expression 3 analysis software package (BioDiscovery, Hawthorne, CA, USA); classification of samples in high vs. low ESR1 groups was performed by comparison to the mean expression level observed in normal tissues plus or minus two standard deviations.
  • mice were implanted subcutaneously with 2x10 6 H460 cells; when tumors became palpable, mice were treated with intraperitoneal injection of either HBSS or 20 mg/kg docetaxel every three days for three cycles. Fulvestrant- treated animals were given a single dose of 250 mg/kg fulvestrant s.c. five days prior to tumor collection. In the combination study, animals were implanted subcutaneously with lxlO 6 H460 cells.
  • Fulvestrant 250 mg/kg was given on days 4 and 1 1 of tumor growth, while docetaxel (20 mg/kg) was given on days 7 and 11 of tumor growth.
  • Tumors were stained using primary antibodies against ESR1 (Abeam), brachyury (MAb 54-1) and fibronectin (GeneTex), and sections were counterstained with haematoxylin.
  • mesenchymal-like cancer cells were generated by single cell-derived culture of lung carcinoma H460 cells.
  • H460-E cells were characterized by low levels of expression of mesenchymal brachyury and fibronectin and high levels of epithelial ZO-1 (Fig. 1A).
  • clone H460-M was considered mesenchymal-like, with high levels of brachyury and fibronectin and very low levels of ZO-1 (Fig. 1A).
  • H460-M was significantly less sensitive than the epithelial counterpart clone (H460-E) to the cytotoxic effect of both brachyury-specific CD8 + cytotoxic T cells and effector NK cells, at all effector-to-target (E:T) ratios evaluated (Fig. I B and C, respectively).
  • H460-M cells exhibited a marked resistance to a range of concentrations of the immune-mediator TRAIL (Fig. ID) or the chemotherapeutic cisplatin (Fig. IE) compared to H460-E cells.
  • Pharmacological Collection was screened to identify clinically-relevant compounds that could enhance the susceptibility of resistant lung cancer cells to immune-mediated lysis.
  • the screen was aimed at identifying compounds that were cytotoxic for TRAIL-treated cells but were devoid of cell toxicity when used alone. Using these selection criteria, 53 hits were identified corresponding to 51 unique compounds (Fig. 2A, larger dots).
  • fulvestrant, selegiline, and midazolam were selected for further analysis (Fig. 2A and Fig. 2B).
  • midazolam has been replaced in the clinic by newer generations of benzodiazepines, clonazepam, diazepam, and lorazepam were further evaluated in secondary assays.
  • Fig. 2C only fulvestrant was confirmed to enhance susceptibility to TRAIL with parental H460 cells, thus being chosen as the lead compound for further studies.
  • fulvestrant is a pure estrogen receptor antagonist that induces receptor degradation. To assess whether the ability of fulvestrant to enhance the sensitivity of mesenchymal-like tumor cells to TRAIL-mediated lysis might be a consequence of its ability to downregulate estrogen receptor levels, its activity was compared with that of 4- hydroxy-tamoxifen, the active metabolite of tamoxifen.
  • H460-E and H460-M cells were pre-treated for 3 days with various concentrations of fulvestrant vs. 4-hydroxy-tamoxifen prior to the addition of TRAIL. Intriguingly, both antagonists failed to modify the cytotoxic response of the epithelial H460-E cells, while fulvestrant (and not 4-hydroxy-tamoxifen) was able to significantly augment the
  • isogenic HI 703 lung carcinoma lines stably transfected with either a control (pCMV) or a brachyury expressing (pBr) vector were generated from which two clonally-derived cell populations characterized by low (pBr-Cll) or high (pBr-C12) levels of brachyury were generated (Fig. 3B).
  • pBr-C12 with the highest expression of brachyury also exhibited mesenchymal features, including high expression of fibronectin (Fig. 3C) and, surprisingly, high ESR1 mRNA levels (Fig. 3D).
  • NK cells In addition to TRAIL, the above observations were extended to include NK cells. As shown in Fig. 3F, H460 lung carcinoma cells pre-treated with 50 or 500 nmol/L fulvestrant were significantly lysed by NK effector cells compared to untreated H460 cells. As the effect of fulvestrant was similar with both doses, all subsequent experiments were conducted with 50 nmol/L fulvestrant, otherwise indicated, which is comparable to the plasma Cmax (-40 nmol/L) for multiple dose steady state observed in patients treated with the drug (Kuter et al., Breast Cancer Res. Treat, 133: 237-46 (2012)). These observations suggested that estrogen signaling might play an important role in protecting mesenchymal- like lung carcinoma cells to immune-mediated attack.
  • This example demonstrates upregulation of ESR1 signaling in chemo-resistant lung cancer cells.
  • HI 703 cells selected in vitro in the presence of a combination of cisplatin and vinorelbine exhibited enhanced expression of T, SNAI2, FN1 and OCLN mRNA (encoding brachyury, slug, fibronectin, and occludin protein, respectively), and had a 672-fold increase in ESRl mRNA levels, compared to control HI 703 cells.
  • chemo-resistant cells also were highly resistant to immune-effector mechanisms, including TRAIL (Fig. 4B) and effector NK cells (Fig. 4C).
  • fulvestrant effectively restored their TRAIL or NK-mediated lysis to levels observed with control HI 703 cells.
  • sensitivity of the HI 703 chemo-resistant cells to a combination of cisplatin and vinorelbine was also reconstituted when the tumor cells were exposed to fulvestrant prior to, and during the cytotoxic assay (Fig 4D).
  • H460 cells were stably modified to overexpress ESR1.
  • high expression of ESR1 significantly decreased the response of H460 cells to NK effector cells.
  • single clonal populations of H460 selected based on the expression of ESR1 demonstrated a direct association between ESR1 level and resistance to immune-mediated lysis.
  • an H460 ESRl-High clone was completely resistant to the effect of a range of concentrations of TRAIL compared to an H460 ESRl-Low clone.
  • ESRl-High clone (Fig. 5D) had significantly higher levels of expression of mesenchymal SNAI1, SNAI2, T, FN1 and VIM mRNA (encoding for snail, slug, brachyury, fibronectin and vimentin, respectively) as compared with the ESRl -Low clone.
  • fulvestrant The role of fulvestrant in EMT modulation was first evaluated with H460 cells treated with fulvestrant in vitro. As shown in Fig. 6 A, fulvestrant markedly reduced the expression of the mesenchymal proteins brachyury, fibronectin and vimentin in H460 cells in a dose-dependent manner. To more directly assess the effects of fulvestrant treatment on the transcriptional activity of the brachyury protein, a luciferase reporter vector was generated (Fig. 6B) containing a promoter with a synthetic brachyury response element consisting of a single brachyury palindromic binding site (Chaffer et al., Science, 331: 1559-64 (201 1)).
  • This construct was transfected into the H460 cell line, and the effect of fulvestrant treatment on brachyury transcriptional activity was measured. A dose-dependent decrease in brachyury activity was observed in response to fulvestrant treatment (Fig. 6C). Further, fulvestrant also was able to reduce, on a dose-dependent fashion, the activity of a brachyury promoter reporter construct (Fig. 6D), thus demonstrating that estrogen signaling directly or indirectly regulates the transcription of the EMT transcription factor brachyury in lung cancer cells.
  • fulvestrant was evaluated in vivo by administration of a single dose fulvestrant to mice bearing lung H460 xenografts.
  • expression of estrogen receptor 1 , brachyury, and fibronectin were evaluated by immunohistochemistry (Fig 6E). Fulvestrant was able to decrease the levels of all three proteins in tumor cells with the most significant reductions of fibronectin and brachyury taking place in tumors where the highest decrease of ESRl levels (tumors T-4 and T-6, Fig. 6E).

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Abstract

L'invention concerne un procédé d'amélioration de la lyse à médiation immunitaire de cellules cancéreuses mésenchymateuses et un procédé de sensibilisation des cellules cancéreuses à une chimiothérapie ou une lyse à médiation immunitaire. Les procédés comprennent l'administration de fulvestrant aux cellules cancéreuses. L'invention concerne également un procédé de traitement d'un cancer pulmonaire comprenant l'administration d'une combinaison de fulvestrant et d'un traitement à médiation immunitaire à un patient.
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