[go: up one dir, main page]

US20190183930A1 - Methods for stem cell transplantation - Google Patents

Methods for stem cell transplantation Download PDF

Info

Publication number
US20190183930A1
US20190183930A1 US15/754,973 US201615754973A US2019183930A1 US 20190183930 A1 US20190183930 A1 US 20190183930A1 US 201615754973 A US201615754973 A US 201615754973A US 2019183930 A1 US2019183930 A1 US 2019183930A1
Authority
US
United States
Prior art keywords
cells
day
canceled
cell
subject
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US15/754,973
Other languages
English (en)
Inventor
Lawrence S LAMB
Shin Mineishi
Ayman SAAD
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
UAB Research Foundation
Original Assignee
UAB Research Foundation
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 UAB Research Foundation filed Critical UAB Research Foundation
Priority to US15/754,973 priority Critical patent/US20190183930A1/en
Assigned to THE UAB RESEARCH FOUNDATION reassignment THE UAB RESEARCH FOUNDATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SAAD, Ayman, MINEISHI, SHIN, LAMB, LAWRENCE S
Publication of US20190183930A1 publication Critical patent/US20190183930A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/193—Colony stimulating factors [CSF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/10—Cellular immunotherapy characterised by the cell type used
    • A61K40/11—T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/20—Cellular immunotherapy characterised by the effect or the function of the cells
    • A61K40/22—Immunosuppressive or immunotolerising
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K40/00—Cellular immunotherapy
    • A61K40/40—Cellular immunotherapy characterised by antigens that are targeted or presented by cells of the immune system
    • A61K40/41—Vertebrate antigens
    • A61K40/418—Antigens related to induction of tolerance to non-self
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/0081—Purging biological preparations of unwanted cells
    • C12N5/0087—Purging against subsets of blood cells, e.g. purging alloreactive T cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2239/00—Indexing codes associated with cellular immunotherapy of group A61K40/00
    • A61K2239/38—Indexing codes associated with cellular immunotherapy of group A61K40/00 characterised by the dose, timing or administration schedule
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

  • Allogeneic hematopoietic stem cell transplantation is a potentially curative treatment for many patients with hematological malignancies.
  • the clinically preferred source for stem cells is a human leukocyte antigen (HLA) matched sibling donor or an HLA-matched unrelated donor.
  • HLA human leukocyte antigen
  • Registry searches can also be inappropriately time-consuming in some high-risk patients. Therefore, alternative sources of HSCT grafts have been clinically used. These options include the use of donor cells from a partially HLA matched (haploidentical) family member. 3
  • Haploidentical HSCT has been shown to achieve long-term survival and cure in patients who require allogeneic HSCT with no HLA-matched donor. 3
  • the success of haploidentical HSCT has been hindered by multiple complications.
  • the HLA disparity between the donor and recipient can induce high risks of graft rejection, graft versus host disease (GvHD), and delayed immune reconstitution with subsequent infectious complications.
  • the use of intense immunosuppression regimens (to prevent GvHD) may, at least in theory, abrogate the graft versus tumor (GvT) effect portending an increased risk of disease relapse.
  • the GvT effect after allo HSCT has been shown to correlate with a decreased risk of relapse.
  • the infused donor T-cells can have beneficial effects (engraftment, immune reconstitution, and GvT) and also exert a harmful (and sometimes fatal) effect of GvHD.
  • beneficial effects engraftment, immune reconstitution, and GvT
  • GvT immune reconstitution
  • researchers have looked at ways to engineer cellular therapies that will provide the optimum ratio of T-cell subsets that may provide a sufficient number of cells to maintain engraftment and optimize GvT effect, while minimizing the allo-reactive T-cells that can lead to GvHD.
  • the present disclosure provides methods and compositions useful in HSCT that maximize a beneficial effect of infused donor T-cells (including, but not limited to, engraftment, immune reconstitution, and GvT) while minimizing a harmful effect (such as, but not limited to, GvHD).
  • the present disclosure provides a method of HSCT using a combination of an in-vivo T-cell depletion method after transplantation of minimally manipulated peripheral blood stem cells (PBSC), with an ex-vivo method of ⁇ T cell enrichment and/or expansion and/or ⁇ T cell depletion to provide improved methods of HSCT.
  • PBSC peripheral blood stem cells
  • the method of HSCT comprises: i) administering to a subject on day 0 a haploidentical hematopoietic stem cell graft infusion comprising PBSC; ii) administering to the subject an agent which provides in vivo T cell depletion; iii) optionally expanding a population of ⁇ T cells ex vivo; and iv) administering to the subject a second graft infusion comprising T cells enriched in ⁇ T cells and depleted in ⁇ T cells.
  • the method of HSCT comprises: i) administering to a subject on day 0 a minimally manipulated haploidentical hematopoietic stem cell graft infusion comprising PBS C; ii) administering to the subject an agent which provides in vivo T cell depletion; iii) optionally expanding a population of ⁇ T cells ex vivo; and iv) administering to the subject a second graft infusion comprising T cells enriched in ⁇ T cells and depleted in ⁇ T cells.
  • the method of HSCT comprises: i) administering to a subject on day 0 a haploidentical hematopoietic stem cell graft infusion comprising PBSC; ii) administering to the subject an agent which provides in vivo T cell depletion; iii) expanding a population of ⁇ T cells ex vivo; iv) administering to the subject a second graft infusion comprising the expanded population of ⁇ T cells, wherein the expanded population of ⁇ T cells is enriched in ⁇ T cells and depleted in ⁇ T cells.
  • the method of HSCT comprises: i) administering to a subject on day 0 a minimally manipulated haploidentical hematopoietic stem cell graft infusion comprising PBSC; ii) administering to the subject an agent which provides in vivo T cell depletion; iii) expanding a population of ⁇ T cells ex vivo; iv) administering to the subject a second graft infusion comprising the expanded population of ⁇ T cells, wherein the expanded population of ⁇ T cells is enriched in ⁇ T cells and depleted in ⁇ T cells.
  • the method of HSCT comprises: i) obtaining a pool of PBSC from a haploidentical donor; ii) splitting the pool of PBSC into a first portion of PBSC to provide a PBSC product and a second portion of PBSC that is manipulated to provide a ⁇ T cell product which is enriched in ⁇ T cells and depleted in ⁇ T cells; iii) administering to a subject on day 0 a hematopoietic stem cell graft infusion comprising the PBSC product; iv) administering to the subject an agent which provides in vivo T cell depletion; v) optionally expanding a population of ⁇ T cells ex vivo in the ⁇ T cell product and vi) administering to the subject a second graft infusion comprising the ⁇ T cell product.
  • the method of HSCT comprises: i) obtaining a pool of PBSC from a haploidentical donor; ii) splitting the pool of PBSC into a first portion of PBSC which is minimally manipulated to provide a PBSC product and a second portion of PBSC that is manipulated to provide a ⁇ T cell product which is enriched in ⁇ T cells and depleted in ⁇ T cells; iii) administering to a subject on day 0 a hematopoietic stem cell graft infusion comprising the PBSC product; iv) administering to the subject an agent which provides in vivo T cell depletion; v) optionally expanding a population of ⁇ T cells ex vivo in the ⁇ T cell product and vi) administering to the subject a second graft infusion comprising the ⁇ T cell product.
  • the method of HSCT comprises: i) obtaining a pool of PBSC from a haploidentical donor; ii) splitting the pool of PBSC into a first portion of PBSC to provide a PBSC product and a second portion of PBSC that is manipulated to provide a ⁇ T cell product which is enriched in ⁇ T cells and depleted in ⁇ T cells; iii) administering to a subject on day 0 a hematopoietic stem cell graft infusion comprising the PBSC product; iv) administering to the subject an agent which provides in vivo T cell depletion; v) expanding a population of ⁇ T cells ex vivo in the ⁇ T cell product and vi) administering to the subject a second graft infusion comprising the ⁇ T cell product.
  • the method of HSCT comprises: i) obtaining a pool of PBSC from a haploidentical donor; ii) splitting the pool of PBSC into a first portion of PBSC which is minimally manipulated to provide a PBSC product and a second portion of PBSC that is manipulated to provide a ⁇ T cell product which is enriched in ⁇ T cells and depleted in ⁇ T cells; iii) administering to a subject on day 0 a hematopoietic stem cell graft infusion comprising the PBSC product; iv) administering to the subject an agent which provides in vivo T cell depletion; v) expanding a population of ⁇ T cells ex vivo in the ⁇ T cell product and vi) administering to the subject a second graft infusion comprising the ⁇ T cell product.
  • the described methods of HSCT will maximize a beneficial effect of infused donor T-cells (including, but not limited to, engraftment, immune reconstitution, and GvT). In certain embodiments of the above aspects, the described method of HSCT will minimize a harmful effect of infused donor T-cells (such as, but not limited to, GvHD). In certain embodiments of the above aspects, a combination of the foregoing is achieved.
  • the PBSC grafts are collected from haploidentical donors and the cell product divided into a minimally manipulated HSCT product that will be administered to the subject on day 0 (as is standard in HSCT) and a ⁇ T cell product that will be administered to the subject after day 0.
  • the ⁇ T cell product is administered to the subject up to 25 days after day 0.
  • ⁇ T cell product is administered to the subject ⁇ 3 days after in vivo T cell depletion is initiated.
  • the ⁇ T cell product is expanded ex vivo to increase the number of ⁇ T cells in the ⁇ T cell product.
  • the ⁇ T cell product is enriched in ⁇ T cells.
  • the ⁇ T cell product is depleted in ⁇ T cells. In certain embodiments, the ⁇ T cell product is expanded ex vivo to increase the number of ⁇ T cells in the ⁇ T cell product and depleted in ⁇ T cells. In certain embodiments, the ⁇ T cell product is enriched in ⁇ T cells and depleted in ⁇ T cells.
  • the methods of the present disclosure may be used in conjunction with any condition for which HSCT is used.
  • the methods of the present disclosure may be used in conjunction with a preparative chemotherapy regimen; such preparative chemotherapy regimen is preferably initiated prior to day 0.
  • the methods of the present disclosure are used in combination with an in vivo T cell depletion protocol which is initiated after day 0.
  • the in vivo T cell depletion protocol is post-transplant administration of cyclophosphamide (CY).
  • the methods of the present disclosure may be used in conjunction with a GvHD prophylaxis regimen; such GvHD prophylaxis regimen is preferably initiated after day 0.
  • the methods of the present disclosure may be used in conjunction with growth factor treatment; such growth factor treatment is preferably initiated after day 0.
  • FIG. 1 Shows one embodiment of a preparative regimen for myeloid diseases using Fludarabine/Busulfan/TBI.
  • FIG. 2 Shows one embodiment of a preparative regimen ALL or Lymphoma patients 40 years old and younger using TBI/cyclophosphamide.
  • FIG. 3 Shows one embodiment of a preparative regimen for ALL or Lymphoma patients older than 40 years of age or at any age with major comorbidities.
  • minimally manipulated means that the PBSC pool isolated from a donor (such as a haploidentical donor) is not subject methods or procedures that alter the relevant biological characteristics of the cell.
  • the PBSC pool isolated from a donor is not subject methods or procedures that enrich and/or deplete a particular population of cells (such as, but not limited to, ⁇ T cells) from the PBSC pool prior to administration to the subject.
  • the term “depleted in” means that the number or concentration of a particular cell type in a population of cells has been decreased (for example as the result of a particular manipulation or procedure) from an initial original level to a reduced second level. The term does not require a complete removal of the particular cell type from the population of cells.
  • a population of T cells is “depleted in” ⁇ T cells if the number or concentration of ⁇ T cells in a composition administered to a subject is decreased as compared to the number or concentration of ⁇ T cells originally present (such as in a pool of PBSCs obtained from a donor).
  • enriched in means that the number or concentration of a particular cell type in a population of cells has been increased (for example as the result of a particular manipulation or procedure) from an initial original level to a higher second level.
  • a population of T cells is “enriched in” ⁇ T cells if the number or concentration of ⁇ T cells in a composition administered to a subject is increased as compared to the number or concentration of ⁇ T cells originally present (such as in a pool of PBSCs obtained from a donor).
  • T-cells The majority ( ⁇ 80%) of infused donor lymphocytes are T-cells (other infused cells are B-cells and NK cells). T-cells have been shown to be the key player in the post-transplant immune phenomena (stem cell engraftment, GvHD, GVT, and immune reconstitution) with B-cells and NK cells likely contributing supportive roles (1, 7).
  • the majority ( ⁇ 95%) of T-cells carries alpha-beta T-cell receptors ( ⁇ -TCR); referred to as alpha-beta T-cells ( ⁇ T-cells).
  • ⁇ TCR alpha-beta T-cell receptors
  • ⁇ T-TCR alpha-beta T-cells
  • a small proportion of T-cells carry a different T-cell receptor, ⁇ -TCR, referred to as gamma-delta T-cells ( ⁇ T cells)
  • the ⁇ T cells have been shown to have an anti-tumor activity. They are considered to be a part of the innate immune system preventing development of new cancer and also protecting from infections via immune surveillance function (8). Unlike the common T-cell subtype, ⁇ T-cells, ⁇ T cells do not require antigen recognition to kill malignant cells (9). Thus, they have been advocated for use against cancer (9).
  • the NK cells another type of innate immune cells, have also shown to have an anti-tumor effect and to promote immune reconstitution after HCT without increasing the risk of GvHD (10, 11).
  • ⁇ T cells have been shown to have an anti-leukemic effect in partially mismatched transplant without increasing the risk of GvHD (12, 13).
  • LFS 5-year leukemia-free survival
  • OS overall survival
  • Haploidentical transplant patients are currently being gathered into a Phase I trial in which patients receive post-transplant cyclophosphamide (CY) following a minimally manipulated graft. A second graft from the same donor is selectively depleted of ⁇ T cells and infused on post-HSCT day +7. To this point, three patients have been enrolled on the study without evidence of GvHD.
  • CY post-transplant cyclophosphamide
  • ⁇ T cells which recognize specific processed peptide antigens presented on MHC molecules by antigen presenting cells (APCs)
  • APCs antigen presenting cells
  • ⁇ T cells appear to directly recognize and respond to a variety of MHC-like stress-induced self-antigens expressed by malignant cells (12-16).
  • ⁇ T cells can recognize malignant cells through less specific mechanisms that require no prior antigen exposure or priming, a function that is shared by other innate immune cells such as macrophages and NK cells (8).
  • ⁇ T cells are not primary initiators of GvHD and may in fact modulate the GvHD activity of ⁇ T cells.
  • Drobyski (25) showed that large doses of
  • IL-2 expanded ⁇ T cells could be infused into lethally irradiated MHC-disparate mice (C57BL/6 [H-2 b ] a BIO.BR [H-2k] and C57BL/6 [H-2 b ] a B6D2F1 [H-2 b/d ]) without causing GvHD.
  • Ellison (29) noted that ⁇ T cells were activated in the GvHD reaction but found no evidence that GvHD was initiated by ⁇ T cells. This work is in agreement with later studies by Drobyski (25) who showed that although activated ⁇ and na ⁇ ve ⁇ T cells exacerbated GvHD when infused together, delaying the infusion of ⁇ T cells by two weeks resulted in improved survival.
  • BMT-CTN Bone Marrow Transplant Clinical Trials Network
  • the present disclosure provides methods of HSCT.
  • the present disclosure provides a method of HSCT using a combination of an in-vivo T-cell depletion method (for example, post-transplant cyclophosphamide), with an ex-vivo method of ⁇ T cell expansion and ⁇ T cell depletion (using, for example the CLINIMACS® System).
  • the in-vivo T-cell depletion (for example, infusion of CY after infusion of a minimally manipulated stem cell graft) depletes (in-vivo) the alloreactive T cells that would otherwise increase the risk of GvHD.
  • the ex-vivo expanded/activated ⁇ T cell product will be selectively depleted of ⁇ T cells but will also include a secondary population of NK cells.
  • the method of HSCT comprises: i) administering to a subject on day 0 a haploidentical hematopoietic stem cell graft infusion comprising PBSC; administering to the subject an agent which provides in vivo T cell depletion; iii) optionally expanding a population of ⁇ T cells ex vivo; and iv) administering to the subject a second graft infusion comprising T cells enriched in ⁇ T cells and depleted in ⁇ T cells.
  • the method of HSCT comprises: i) administering to a subject on day 0 a minimally manipulated haploidentical hematopoietic stem cell graft infusion comprising PBSC; ii) administering to the subject an agent which provides in vivo T cell depletion; iii) optionally expanding a population of ⁇ T cells ex vivo; and iv) administering to the subject a second graft infusion comprising T cells enriched in ⁇ T cells and depleted in ⁇ T cells.
  • the method of HSCT comprises: i) administering to a subject on day 0 a haploidentical hematopoietic stem cell graft infusion comprising PBSC; ii) administering to the subject an agent which provides in vivo T cell depletion; iii) expanding a population of ⁇ T cells ex vivo; iv) administering to the subject a second graft infusion comprising the expanded population of ⁇ T cells, wherein the expanded population of ⁇ T cells is enriched in ⁇ T cells and depleted in ⁇ T cells.
  • the method of HSCT comprises: i) administering to a subject on day 0 a minimally manipulated haploidentical hematopoietic stem cell graft infusion comprising PBSC; ii) administering to the subject an agent which provides in vivo T cell depletion; iii) expanding a population of ⁇ T cells ex vivo; iv) administering to the subject a second graft infusion comprising the expanded population of ⁇ T cells, wherein the expanded population of ⁇ T cells is enriched in ⁇ T cells and depleted in ⁇ T cells.
  • the method of HSCT comprises: i) obtaining a pool of PBSC from a haploidentical donor; ii) splitting the pool of PBSC into a first portion of PBSC to provide a PBSC product and a second portion of PBSC that is manipulated to provide a ⁇ T cell product which is enriched in ⁇ T cells and depleted in ⁇ T cells; iii) administering to a subject on day 0 a hematopoietic stem cell graft infusion comprising the PBSC product; iv) administering to the subject an agent which provides in vivo T cell depletion; v) optionally expanding a population of ⁇ T cells ex vivo in the ⁇ T cell product and vi) administering to the subject a second graft infusion comprising the ⁇ T cell product.
  • the method of HSCT comprises: i) obtaining a pool of PBSC from a haploidentical donor; ii) splitting the pool of PBSC into a first portion of PBSC which is minimally manipulated to provide a PBSC product and a second portion of PBSC that is manipulated to provide a ⁇ T cell product which is enriched in ⁇ T cells and depleted in ⁇ T cells; iii) administering to a subject on day 0 a hematopoietic stem cell graft infusion comprising the PBSC product; iv) administering to the subject an agent which provides in vivo T cell depletion; v) optionally expanding a population of ⁇ T cells ex vivo in the ⁇ T cell product and vi) administering to the subject a second graft infusion comprising the ⁇ T cell product.
  • the method of HSCT comprises: i) obtaining a pool of PBSC from a haploidentical donor; ii) splitting the pool of PBSC into a first portion of PBSC to provide a PBSC product and a second portion of PBSC that is manipulated to provide a ⁇ T cell product which is enriched in ⁇ T cells and depleted in ⁇ T cells; iii) administering to a subject on day 0 a hematopoietic stem cell graft infusion comprising the PBSC product; iv) administering to the subject an agent which provides in vivo T cell depletion; v) expanding a population of ⁇ T cells ex vivo in the ⁇ T cell product and vi) administering to the subject a second graft infusion comprising the ⁇ T cell product.
  • the method of HSCT comprises: i) obtaining a pool of PBSC from a haploidentical donor; ii) splitting the pool of PBSC into a first portion of PBSC which is minimally manipulated to provide a PBSC product and a second portion of PBSC that is manipulated to provide a ⁇ T cell product which is enriched in ⁇ T cells and depleted in ⁇ T cells; iii) administering to a subject on day 0 a hematopoietic stem cell graft infusion comprising the PBSC product; iv) administering to the subject an agent which provides in vivo T cell depletion; v) expanding a population of ⁇ T cells ex vivo in the ⁇ T cell product and vi) administering to the subject a second graft infusion comprising the ⁇ T cell product.
  • the method comprises administering to a subject a haploidentical PBSC infusion on day 0 followed by a ⁇ T cell infusion at +7 to plus +25 days.
  • the method further comprises administering a preparative chemotherapy regimen prior to day 0.
  • the method further comprises administering a T-cell depletion protocol after day 0.
  • the method further comprises administering a GvHD prophylaxis regimen after day 0.
  • the method further comprises administering a growth factor after day 0.
  • the method further comprises a combination of at least two of: (i) administering a preparative chemotherapy regimen prior to day 0; (ii) administering a T-cell depletion protocol after day 0; (iii) administering a GvHD prophylaxis regimen after day 0; and (iv) administering a growth factor after day 0.
  • the method further comprises a combination of at least three of: (i) administering a preparative chemotherapy regimen prior to day 0; (ii) administering a T-cell depletion protocol after day 0; (iii) administering a GvHD prophylaxis regimen after day 0; and (iv) administering a growth factor after day 0.
  • the method further comprises a combination of each of: (i) administering a preparative chemotherapy regimen prior to day 0; (ii) administering a T-cell depletion protocol after day 0; (iii) administering a GvHD prophylaxis regimen after day 0; and (iv) administering a growth factor after day 0.
  • the described method of HSCT will maximize a beneficial effect of infused donor T-cells (including, but not limited to, engraftment, immune reconstitution, and GvT). In another embodiment of any of the foregoing, the described method of HSCT will minimize a harmful effect of infused donor T-cells (such as, but not limited to, GvHD). In yet another embodiment of any of the foregoing, a combination of the foregoing is achieved by the method.
  • PBSC grafts are collected from haploidentical donors and the cell product divided into an minimally manipulated HCT product that will be given on transplant day (as is standard in HSCT) and a ⁇ T cell product that will be given up to 25 days after the transplant, for example, in one embodiment, ⁇ 3 days after.
  • HCT minimally manipulated HCT
  • ⁇ T cell product that will be given up to 25 days after the transplant, for example, in one embodiment, ⁇ 3 days after.
  • the number of PBSC infused in the haploidentical hematopoietic stem cell graft infusion is as known in the art.
  • the selection of the number of cells to be infused may depend on a number of factors as is known in the art, such as but not limited to, the disease or condition to be treated and the condition of the subject.
  • up to 5 ⁇ 10 8 ⁇ T cells are infused in the second graft infusion. In one embodiment any of the foregoing, 1 ⁇ 10 7 ⁇ T cells are infused in the second graft infusion. In one embodiment any of the foregoing, up to 5 ⁇ 10 6 ⁇ T cells are infused in the second graft infusion. In one embodiment of any of the foregoing, up to 5 ⁇ 10 8 ⁇ T cells/kg are infused in the second graft infusion. In one embodiment any of the foregoing, 1 ⁇ 10 7 ⁇ T cells/kg are infused in the second graft infusion.
  • any of the foregoing up to 5 ⁇ 10 6 ⁇ T cells/kg are infused in the second graft infusion.
  • the selection of the number of cells to be infused may depend on a number of factors as is known in the art, such as but not limited to, the disease or condition to be treated and the condition of the subject.
  • the second graft infusion or the ⁇ T cell product contains ⁇ 60% ⁇ T cells. In one embodiment, the second graft infusion or the ⁇ T cell product contains ⁇ 60% ⁇ T cells and ⁇ 5% ⁇ T. In one embodiment, the second graft infusion or the ⁇ T cell product contains ⁇ 60% ⁇ T cells, ⁇ 5% ⁇ T cells and ⁇ 25% NK cells.
  • the methods of the present disclosure may be used in conjunction with any condition for which HSCT is used.
  • the condition is selected from one of the following: (i) patients with neoplastic hematological disorders with indication of allogeneic transplant according to the National Comprehensive Cancer Network (NCCN) or other standard guidelines as follows; (a) Acute lymphoblastic leukemia [ALL] 25 with high-risk features or relapsed disease (relapsed ALL); (b) Hodgkin 26 or Non-Hodgkin lymphoma 27 [HL or NHL]: relapsed disease where remission duration is less than 1 year, relapse after previous autologous transplant, or failure to achieve complete response (CR) with chemotherapy; and (c) Myeloid malignancy (such as for example acute myeloid leukemia [AML] 28 with intermediate/high-risk features (per NCCN criteria) or relapsed disease, OR chronic myeloid leukemia [CML] 29 in he
  • myeloid disorder such as for example myelodysplastic syndrome [MDS] 30 with intermediate/high risk features or refractory disease or myeloproliferative disorder; primary or secondary if high-risk features or refractory disease
  • other conditions such as, but not limited to, astrocytoma, ATRT (Atypical Teratoid Rhaboid Tumor), brain stem glioma, choroid plexus tumors, carcinoma and papilloma, craniopharyngioma, desmoplastic infantile astrocytoma, germ cell tumor, medulloblastoma, neurofibromatosis, oligodendroglioma, optic glioma, neuroblastoma, Ewing's Sarcoma, and PNET (Primitive Neuroectodermal Tumor).
  • ATRT Alternatoid Rhaboid Tumor
  • brain stem glioma choroid plexus tumors, carcinoma and papilloma
  • the methods of the present disclosure may be used in conjunction with a preparative chemotherapy regimen.
  • the preparative chemotherapy regimen is any known in the art.
  • NRM non-relapse mortality
  • the methods of the present disclosure are used in combination with a in vivo T cell depletion protocol.
  • any such protocol known in the art may be used.
  • the T cell depletion protocol is cyclophosphamide treatment between days +1 and +10.
  • the T cell depletion protocol is cyclophosphamide treatment at between 30 and 70 mg/kg or 50 mg/kg.
  • the T cell depletion protocol is cyclophosphamide treatment at between 30 and 70 mg/kg or 50 mg/kg at days +3 and +4.
  • a GvHD prophylaxis regimen is used.
  • the GvHD prophylaxis regimen is any known in the art.
  • the GvHD prophylaxis regimen provides for a decreased number of agents and/or a reduced concentration of one or more agents to be used, wherein the agent provides for suppression of the immune system.
  • the GvHD prophylaxis regimen is one of the following: (i) CELLCEPT® (mycophenolate mofetil) will be given as 15 mg/kg orally (PO) 3 times daily (maximum daily dose of 3 gm) starting day +5 to day +35.
  • An intravenous formulation may be used as per physician discretion until reliable PO intake of the patient is established.
  • Tacrolimus will be given as 0.03 mg/kg/day (dosing may be adjusted as is standard for drug interactions with concurrent medications) IV infusion beginning on day +5 and converted to oral tacrolimus when PO intake is tolerated. Tacrolimus will be continued until day +100 and then may be tapered to none by day +180 if there is no evidence of active GvHD; (ii) Tacrolimus will be given as 0.03 mg/kg/day (dosing may be adjusted as is standard for drug interactions with concurrent medications) IV infusion beginning on day +5 and converted to oral tacrolimus when PO intake is tolerated.
  • Tacrolimus will be continued until day +100 and then may be tapered to none by day +180 if there is no evidence of active GvHD; or (iii) Tacrolimus will be given as 0.03 mg/kg/day (dosing may be adjusted as is standard for drug interactions with concurrent medications) IV infusion beginning on day +5 and converted to oral tacrolimus when PO intake is tolerated. Tacrolimus will be continued until day +50 and then may be tapered to none by day +100 if there is no evidence of active GvHD.
  • the methods of the present disclosure may be used in conjunction with growth factor treatment.
  • any growth factor treatment regimen may be used.
  • the growth factor is granulocyte-colony stimulating factor (G-CSF).
  • G-CSF is administered from day +5 to about day +20 or from day +5 to about day +15.
  • the G-CSF is administered at about 5 mcg/kg on day +5 after transplant until neutrophil engraftment.
  • ⁇ T cell depletion Methods for ⁇ T cell depletion are known in the art and any method known in the art may be used. In one embodiment, the following method of ⁇ T cell depletion is used.
  • the CLINIMACS® device with the ⁇ / ⁇ TCR Reagent Kit and other associated reagents is used for ⁇ T cell depletion.
  • CLINIMACS® ⁇ / ⁇ TCR Reagent is a sterile monoclonal antibody reagent specific for ⁇ cells. The depletion of the ⁇ T-cells will be performed according to the manufacturer's instructions and as previously described (16).
  • the leukapheresis/ex-vivo expanded product are incubated with the appropriate antibodies that are conjugated to magnetic particles and then are processed using the CLINIMACS® device (Miltenyi Biotec).
  • CLINIMACS® plus Instrument is a software-controlled instrument that processes the blood sample (cell product).
  • the CLINIMACS® Tubing Set is a single-use, sterile, disposable tubing set with proprietary cell selection columns.
  • the CLINIMACS® PBS/EDTA Buffer is a sterile, isotonic, phosphate buffered, 1 mM EDTA saline solution is used as external wash and transport fluid for the in vitro preparation of blood cells.
  • peripheral blood mononuclear cells are obtained via a peripheral blood draw or leukapheresis.
  • the PBMC product is placed into culture at a density of 1-2 ⁇ 10 6 /mL with addition of 2 mM ZOMETA® (Novartis, Inc.; zoledronic acid) and 100 u/mL Interleuken-2 (IL-2 Miltenyi Biotec, Bergish Gladbach, GERMANY) and appropriate GMP-grade base media culture or bioreactor system that allows monocytes to adhere (e.g. tissue culture plastic or the PRODIGY® bioreactor system (Miltenyi Biotech). Following 14 days of culture the cells are harvested and depleted of ⁇ T cells.
  • ⁇ T cell depletion Preferably, the following method of ⁇ T cell depletion is used.
  • the PRODIGY® OR CLINIMACS® device with the ⁇ / ⁇ TCR Reagent Kit and other associated reagents is used for ⁇ T cell depletion.
  • CLINIMACS® ⁇ / ⁇ TCR Reagent is a sterile monoclonal antibody reagent specific for ⁇ cells.
  • the depletion of the ⁇ T-cells is performed according to the manufacturer's instructions and as previously described (16). In brief, the leukapheresis/ex-vivo expanded product is incubated with the appropriate antibodies that are conjugated to magnetic particles and then is processed using the PRODIGY® or CLINIMACS® device (Miltenyi Biotec).
  • CLINIMACS® plus Instrument is a software-controlled instrument that processes the blood sample (cell product).
  • the PRODIGY® and CLINIMACS® Tubing Sets are single-use, sterile, disposable tubing sets with proprietary cell selection columns.
  • the CLINIMACS® PBS/EDTA Buffer is a sterile, isotonic, phosphate buffered, 1 mM EDTA saline solution is used as external wash and transport fluid for the in vitro preparation of blood cells.
  • Eligibility criteria for the study are as follows: (i) Patients with neoplastic hematological disorders with indication of allogeneic transplant according to the National Comprehensive Cancer Network (NCCN) or other standard guidelines as follows; (a) Acute lymphoblastic leukemia [ALL] 25 with high-risk features or relapsed disease; (b) Hodgkin 26 or Non-Hodgkin lymphoma 27 [HL or NHL]: relapsed disease where remission duration is less than 1 year, relapse after previous autologous transplant, or failure to achieve CR with chemotherapy; and (c) Myeloid malignancy (acute myeloid leukemia [AML] 28 with intermediate/high-risk features (per NCCN criteria) or relapsed disease, OR chronic myeloid leukemia [CML] 29 in hematological remission or chronic phase).
  • NCCN National Comprehensive Cancer Network
  • myeloid disorder myelodysplastic syndrome [MDS] 30 with intermediate/high risk features or refractory disease or myeloproliferative disorder; primary or secondary if high-risk features or refractory disease
  • MDS myeloid disorder
  • Age Criteria 19 to 65 years in age
  • Organ Function Criteria The following organ function testing should be done within 35 days before study registration: (a) Cardiac: LVEF of 50% or above, by MUGA or Echocardiogram; (b) Pulmonary: FVC, FEV1 and DLCO (corrected) should be 50% or above of expected; (c) Renal: serum creatinine level to be ⁇ 2 mg/dl or estimated creatinine clearance (CrCl) must be equal or greater than 40 mL/min/1.73 m 2 as calculated by the Cockcroft-Gault Formula; and (d) Hepatic: serum bilirubin ⁇ 1.5 ⁇ upper limit of
  • HLA typing A, B, C and DRB1 typed as high resolution
  • Suitable Donor Medically cleared to donate
  • Eligible Donor Meets all donor screening and testing requirements related to transmission of infectious disease.
  • the methods disclosed will be used to treat a variety of conditions. Depending on the condition to be treated, one of the following preparative regimens will be used.
  • the Fludarabine/Busulfan/total body irradiation preparative therapy is used.
  • This regimen is a modified Fludarabine plus Busulfan preparative regimen.
  • myeloablative Fludarabine plus Busulfan regimen is used, a total dose of busulfan that achieves an AUC (area under the concentration curve) of 20,000 is generally targeted. Since the protocols are adding post-transplant CY the busulfan target will be reduced to 16,000 AUC to minimize regimen related toxicity. Seizure prophylaxis will be administered per institutional guidelines while on busulfan. TBI of 400 cGy (given as 200 cGy ⁇ 2) will be given to achieve adequate immunosuppression to allow engraftment.
  • Post-transplant CY of 50 mg/kg on Day +3 and +4 will also be given.
  • Patients will receive MESNA (an organosulfur compound used as an adjuvant in cancer chemotherapy involving cyclophosphamide and ifosfamide for renal protection) and hydration for prophylaxis of hemorrhagic cystitis as per institutional guidelines.
  • MESNA an organosulfur compound used as an adjuvant in cancer chemotherapy involving cyclophosphamide and ifosfamide for renal protection
  • hydration for prophylaxis of hemorrhagic cystitis as per institutional guidelines. The regimen is further described below and illustrated in FIG. 1 .
  • the standard myeloablative regimen for these patients is TBI 1,200 cGy and CY 60 mg/kg ⁇ 2 days.
  • the TBI dose will remain the same, but the pre-transplant CY dose will be decreased to 20 mg/kg on Day ⁇ 2, and the post-transplant CY dose will be decreased to 50 mg/kg on Day +3 and +4.
  • the total dose of CY is unchanged in this regimen.
  • Patients will receive MESNA and hydration for prophylaxis of hemorrhagic cystitis as per institutional guidelines. The regimen is further described below and illustrated in FIG. 2 .
  • the Fludarabine/TBI preparative regimen will be used for ALL or lymphoma in patients who are older than 40 years, or at any age with major comorbidities that portends high non-relapse mortality (NRM) with high intensity Cy/TBI. These patients will receive Fludarabine 40 mg/m 2 ⁇ 4 days plus TBI 800 cGy instead of the usual 1,200 cGy. Post-transplant CY of 50 mg/kg on Day +3 and +4 will be given. Patient will receive MESNA and hydration for prophylaxis of hemorrhagic cystitis as per institutional guidelines. The regimen is further described below and illustrated in FIG. 3 .
  • Body weight is calculated as follows:
  • IBW Ideal Body Weight
  • donors are screened for eligibility and suitability for allogeneic hematopoietic stem cell donation according to institutional procedures.
  • the suitable and eligible haploidentical donor will undergo peripheral blood apheresis for the collection of stem cells on the day prior to transplant targeting a CD34+ cell dose of >5 ⁇ 10 6 cells/kg of recipient weight (more than 4 ⁇ 10 6 cells/kg).
  • a portion of the product containing a minimum of 1 ⁇ 10 5 ⁇ T cells/kg will be removed for alpha/beta T cell depletion without reducing the transplant product below a CD34 dose of 4 ⁇ 10 6 CD34+ cells/kg.
  • the manipulated fraction will be cryopreserved and stored until confirmation of neutrophil engraftment. If the total stem cell number collected is less than 5 ⁇ 10 6 cells/kg and/or the required ⁇ T cell dose cannot be obtained without reducing the CD34 dose below the 4 ⁇ 10 6 cells/kg, then the product will not be split for additional processing and the patient will be taken off of the study. If a participant is taken off of study before receiving the product, they will receive the post-transplant Cytoxan as per their assigned preparative regimen and continue to be followed for relapse.
  • donors will be screened for eligibility and suitability for allogeneic hematopoietic stem cell donation according to institutional procedures.
  • the suitable and eligible haploidentical donor will undergo peripheral blood apheresis for the collection of stem cells 8 ⁇ 1 days prior to transplant. This product will be designated for cell therapy product. Following this collection, the donor will be mobilized for a collection targeting a CD34+ cell dose of ⁇ 4 ⁇ 10 6 cells/kg).
  • ⁇ T cell expansion protocols manufacturing will be performed in a standard biological safety cabinet in classified ISO 7 space under cGMP/cGMP manufacturing protocols.
  • Donor apheresis product will be resuspended at 1.0-2.0 ⁇ 10 6 /ml in commercial GMP grade T cell expansion medium with or without autologous serum, 2 ⁇ M Zoledronate (Novartis Oncology; East Hanover, N.J.)+50 u/ml GMP grade IL-2 (Miltenyi Biotec)
  • the culture is maintained at the original density for 14 days with addition of 50 u/ml IL-2 on post-culture days 2, 6, and 10 and addition of complete media as determined by pH and cell density.
  • Composition, purity, and viability are determined by flow cytometry at day 0, +7 and +14 following initiation of culture.
  • ⁇ T cells are depleted using the CLINIMACS′, PRODIGY® (Miltenyi Biotec, Auburn, Calif.) or other suitable bioreactor/cell separation system as described on Day +14 ⁇ 3.
  • a final viability determination is obtained by flow cytometric analysis of To Pro Iodide incorporation or other cell viability stain.
  • Our release criteria for the final product are ⁇ 60% ⁇ T cells, ⁇ 5% ⁇ T cells and ⁇ 25% NK cells to be acceptable for infusion. Viability must be confirmed as ⁇ 70% to release the product for infusion. Product with ⁇ 70% viability will require exceptional release. Potency of the cell product is determined using in vitro cytotoxicity assays against K562 cells.
  • DMSO dimethyl sulfoxide
  • MESNA Infusion of post-transplant CY (50 mg/kg) will take place on day +3 and day +4. MESNA will be administered as per institutional guidelines to prevent hemorrhagic cystitis.
  • the ⁇ T cell infusion will take place at any time from day +7 following transplant to day +3 following confirmation of neutrophil engraftment. This timing will permit infusion of the ⁇ T cell infusion after complete CY washout.
  • the product infusion will be performed as per the program's standard order set for the post-transplant infusion of donor cells.
  • infusion of the ⁇ T cell infusion may be withheld for 2 days (until day 9) at the attending physician's discretion. Also, if the patient develops renal insufficiency after post-transplant CY, infusion can be delayed until day 9 to ensure CY is cleared before ⁇ T cell infusion.
  • the infusion strategy will be as follows. Using a standard 3+3 Phase I escalation scheme, subjects will receive a fixed dose of 1 ⁇ 10 7 ⁇ T cells/kg. The first three subjects will receive a complete post-HSCT immunosuppression regimen as described above. The first patient of each group will undergo observation for 90 days prior to accruing the next patient into the protocol.
  • GvHD prophylaxis will consists of post-transplant CY (50 mg/kg IV on Day +3 and day +4 post-transplant).
  • Other GvHD prophylaxis will include mycophenolate mofetil (MMF, CELLCEPT®) and a calcineurin inhibitor, such as tacrolimus, as needed.
  • MMF mycophenolate mofetil
  • CELLCEPT® mycophenolate mofetil
  • tacrolimus calcineurin inhibitor
  • the methods of the present disclosure allow for a reduced GvHD prophylaxis regimen.
  • the GvHD regimen is as follows.
  • CELLCEPT® will be given as 15 mg/kg PO 3 times daily (maximum daily dose of 3 gm) starting day +5 to day +35.
  • An intravenous formulation may be used as per physician discretion until reliable PO intake of the patient is established.
  • Tacrolimus will be given as 0.03 mg/kg/day (dosing may be adjusted as is standard for drug interactions with concurrent medications) IV infusion beginning on day +5 and converted to oral tacrolimus when PO intake is tolerated. Tacrolimus will be continued until day +100 and then may be tapered to none by day +180 if there is no evidence of active GvHD.
  • the GvHD regimen is as follows. Tacrolimus will be given as 0.03 mg/kg/day (dosing may be adjusted as is standard for drug interactions with concurrent medications) IV infusion beginning on day +5 and converted to oral tacrolimus when PO intake is tolerated. Tacrolimus will be continued until day +100 and then may be tapered to none by day +180 if there is no evidence of active GvHD. In one aspect of this embodiment, the above regimen is utilized if no dose limiting toxicity is observed with the regimen in the preceding paragraph.
  • the GvHD regimen is as follows. Tacrolimus will be given as 0.03 mg/kg/day (dosing may be adjusted as is standard for drug interactions with concurrent medications) IV infusion beginning on day +5 and converted to oral tacrolimus when PO intake is tolerated. Tacrolimus will be continued until day +50 and then may be tapered to none by day +100 if there is no evidence of active GvHD. In one aspect of this embodiment, the above regimen is utilized if no dose limiting toxicity is observed with the regimen in the preceding paragraph.
  • a GvHD prophylaxis method that utilizes a minimum of agents and/or concentrations may be beneficially identified and used in combination with the methods of the present disclosure.
  • Infection prophylaxis will be carried out with anti-fungal, anti-bacterial, PCP, and anti-viral therapies as per institutional guidelines. Cytomegalovirus preemptive therapy will be followed with weekly CMV antigen screens or PCR monitoring starting approximately day +20 and continuing until the patient is off of immunosuppression. HHV6, EBV, and adenovirus PCR will be monitored at a minimum of every other week starting at approximately day +20 and continuing until the patient is off of immunosuppression.
  • Tacrolimus 0.03 mg/kg/day IV day +5 to oral to day +180 with taper at +100 ⁇ 1 6 1 or 2 Expand to a total of 10 subjects in Cohort ⁇ 1 (only accrues if cohort 1 exceeds MTD) 3 or more Maximum dose exceeded; Close trial and reevaluate strategy 1 (starting cohort) 3 0 Taper immunosuppression to ⁇ T cells: 1 ⁇ 10 7 next cohort cells/kg 1 Continue accrual MMF: 45 mg/kg/ 2 Maximum dose exceeded; day +5 to Deescalate to cohort ⁇ 1 day +35.
  • Tacrolimus 0.03 mg/kg/day IV day +5 to oral to day +180 with taper at +100 1 6 1 or 2 Advance to next cohort 3 or more Maximum dose exceeded; Deescalate to cohort ⁇ 1 2 ⁇ T cells: 3 0 Taper immunosuppression to 1 ⁇ 10 7 cells/kg next cohort Tacrolimus: 0.03 1 Continue accrual mg/kg/day IV 2 Maximum dose exceeded; day +5 to oral MTD is dose for Cohort 1 to day +180 and accrual to a total with taper of 10 subjects in at +100 Cohort 1 2 6 1 or 2 Advance to next cohort 3 or more Maximum dose exceeded; MTD is dose for Cohort 1 and accrual to a total of 10 subjects in Cohort 1 3 3 0 or 1 Continue accrual ⁇ T cells: 2 Maximum dose exceeded; 1 ⁇ 10 7 cells/kg MTD is dose for Cohort 2 Tacrolimus: 0.03 and accrual to a total mg/kg/day IV of 10 subjects in day +5 to oral Cohort 2 to day +100 with taper at +50 3 6
  • haploidentical transplant patients will be started on G-CSF 5 mcg/kg on day +5 after transplant until neutrophil engraftment.
  • allogeneic transplant recipients are recommended to have the following as appropriate for pre-transplant work-up: infectious disease markers (Hep A, Hep B, Hep C, HTLV, HIV, RPR, West Nile Virus, VZV, CMV, HSV, Toxoplasma IgG, GM assay); pregnancy screening; renal and liver functions lab panels; review of mammogram in female patients greater than 40 years of age; review of colonoscopy, or other appropriate GI screening, in patients greater than 50 years of age; review of PSA levels in males greater than 50 years of age; review of dental status; and review and evaluation of non-malignancy related co-morbid conditions.
  • infectious disease markers Hep A, Hep B, Hep C, HTLV, HIV, RPR, West Nile Virus, VZV, CMV, HSV, Toxoplasma IgG, GM assay
  • pregnancy screening renal and liver functions lab panels
  • Disease Status As indicated by disease type and site, appropriate testing will be used to assess for disease status after transplant.
  • Bone marrow aspirate and biopsy specimen will be collected for morphology examination and cytogenetics at day +30 ( ⁇ 7), day +100 ( ⁇ 14), day +180 ( ⁇ 21), and 1 year ( ⁇ 45 days) post-transplant for all patients who are clinically stable and who have not demonstrated disease progression by that time point.
  • a unilateral marrow aspirate will be collected whenever a relapse is suspected.
  • CT scans or Whole Body CT/PET scans will be performed at day +100 ( ⁇ 14), day +180 ( ⁇ 21), and 1 year ( ⁇ 45 days) post-transplant for all patients who are clinically stable and who have not demonstrated disease progression by that time point.
  • CT scans or Whole Body CT/PET scans will be performed at day +100 ( ⁇ 14), day +180 ( ⁇ 21), and 1 year ( ⁇ 45 days) post-transplant if appropriate and/or bone marrow aspirate and biopsy specimens will be collected for morphology examination and cytogenetics at day +30 ( ⁇ 7), day +100 ( ⁇ 14), day +180 ( ⁇ 21), and 1 year ( ⁇ 45 days) for all patients who are clinically stable and who have not demonstrated disease progression by that time point.
  • relapse is defined by either morphological or cytogenetic evidence of disease in leukemia, or radiologic evidence (including the recurrence of fluoro-deoxyglucose [FDG]-avid lesions on PET scan) of progressive lymphoma.
  • FDG fluoro-deoxyglucose
  • Immune Reconstitution studies will be performed as per BMT standard and/or as clinically indicated.
  • the recommended timing of the labs is at Day +30 ( ⁇ 7), Day +60 ( ⁇ 7), Day +100 ( ⁇ 14), Day +180 ( ⁇ 21), and at 1 year ( ⁇ 45 days) post-transplant.
  • This panel will include measurement of the percentage and absolute count of CD3+, CD4+, CD8+, CD56+, CD19+, Treg (CD4+/CD25+) effector/memory, and GD T-cells.
  • Chimerism studies will be performed as per BMT standard to evaluate for sustained engraftment.
  • the recommended timing of the labs is at Day +30 ( ⁇ 7), Day +60 ( ⁇ 7), Day +100 ( ⁇ 14), Day +180 ( ⁇ 21), and at 1 year ( ⁇ 45 days) post-transplant.
  • the patient will have cardiac function evaluation (Echocardiogram or MUGA scan), Pulmonary Function Tests (FVC, FEV1, and DLCO) and endocrine function tests (Thyroid Function Tests including TSH and free T4, and Random cortisol level) at one year after transplant. PFTs will be repeated yearly thereafter.
  • cardiac function evaluation Echocardiogram or MUGA scan
  • Pulmonary Function Tests FVC, FEV1, and DLCO
  • endocrine function tests thyroid Function Tests including TSH and free T4, and Random cortisol level
  • the study period is from the beginning of conditioning to day 100 post-transplant.
  • the patient will be followed at least for 2 years after transplant for survival and relapse.
  • the post 1 year follow-up interval is determined as clinically necessary.
  • the patient who relapses after transplant will be followed only for survival.
  • Cytarabine (1- ⁇ -D-Arabinofuranosylcytosine) is an antineoplastic drug of formula C 9 H 13 N 3 O 5 (M.W. 243.22) used as a sterile solution for intravenous, intrathecal or subcutaneous administration. Cytarabine injection in combination with other approved anti-cancer drugs is indicated for remission induction in acute non-lymphocytic leukemia of adults and pediatric patients. It has also been found useful in the treatment of acute non-lymphocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, and the blast phase of chronic myelocytic leukemia.
  • Cytarabine injection is indicated in the prophylaxis and treatment of meningeal leukemia. It exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions blocking the progression of cells from the G1 phase to the S-phase. Although the mechanism of action is not completely understood, it appears that Cytarabine acts through the inhibition of DNA polymerase.
  • Cyclophosphamide (Cytoxan, CY).
  • Cyclophosphamide is a synthetic antineoplastic drug chemically recognized as 2-[bis(2-cholorethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxide monohydrate.
  • the molecular formula of CY is C 7 H 15 Cl 2 N 2 O 2 P.H 2 O with a molecular weight of 279.1.
  • CY for parenteral use must be prepared by either adding 0.9% sodium chloride solution, if injected directly, or sterile water, if infused. Constituted in water, CY is hypotonic; hence, it should not be injected directly. Solutions of CY with sodium chloride solution may be injected intravenously, intramuscularly, intraperitoneally, or intrapleurally. Constituted cylophosphamide is physically and chemically stable for 24 hours at room temperature or six days refrigerated. Prepared solutions do not contain any microbial preservative; hence, sterility of the solutions should be monitored.
  • Fludarabine phosphate is an antimetabolite with the chemical name 9H-Purin-6-amine, 2-fluoro-9-(5-0-phosphono-0-D-arabino-furanosyl) (2-fluoro-ara-AMP).
  • the molecular formula is C 10 H 13 FN 5 O 7 P with a molecular weight of 365.2.
  • IV fludarabine is prepared by adding sterile water to the white solid cake. Reconstituted in 2 mL of sterile water, the solid cake produces a solution with an approximate concentration of 25 mg/mL fludarabine phosphate.
  • Reconstituted IV fludarabine contains no antimicrobial preservative; hence, it should be utilized within 8 hours of reconstitution. DO NOT infuse concomitantly with another intravenous solution of unknown compatibility.
  • Busulfan is a bifunctional alkylating agent known chemically as 1,4-butanediol, dimethanesulfonate with a molecular formula of CH 3 SO 2 O(CH 2 ) 4 OSO 2 CH 3 and a molecular weight of 246 g/mole.
  • IV busulfan must be diluted prior to use with either NS or D5W.
  • the diluent quantity should be 10 times the volume of BUSULFEX®, so that the final concentration of busulfan is approximately 0.5 mg/mL.
  • Infusion pumps should be used to administer the diluted busulfan solution. DO NOT infuse concomitantly with another intravenous solution of unknown compatibility. Warning: Rapid infusion of IV busulfan has not been tested and is not recommended. Busulfan is prepared and administered according to institutional guidelines.
  • Tacrolimus is a macrolide immunosuppressant produced by Stretocyces Tsukubaensis. Tacrolimus has an empirical formulation of C 44 H 69 NO 12 —H 2 O and a formula weight of 822.05. Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, freely soluble in ethanol, and very soluble in methanol and chloroform. Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is not known. Experimental evidence suggests that tacrolimus binds to an intracellular protein, FKBP-12.
  • a complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited.
  • This effect may prevent the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines (such as interleukin-2, gamma interferon).
  • lymphokines such as interleukin-2, gamma interferon.
  • the net result is the inhibition of T-lymphocyte activation (i.e., immunosuppression).
  • Tacrolimus PROGRAF® injection
  • Tacrolimus must be diluted with NS or D5W before use.
  • Tacrolimus is administered as a continuous infusion. Oral preparation will be administered on empty stomach every 12 hours.
  • MMF Mycophenolate Mofetil
  • CELLCEPT® mycophenolate mofetil
  • MMF 2-morpholinoethyl ester of mycophenolic acid
  • IMPDH inosine monophosphate dehydrogenase
  • MMF 2-morpholinoethyl
  • E 2-morpholinoethyl-6-(1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoate. It has an empirical formula of C 23 H 31 NO 7 and a molecular weight of 433.50.
  • Mycophenolate mofetil is a white to off-white crystalline powder.
  • Oral dosage formulations should be administered on an empty stomach to avoid variability in MPA absorption.
  • the oral solution may be administered via a nasogastric tube (minimum 8 French, 1.7 mm interior diameter); oral suspension should not be mixed with other medications. Delayed release tablets should not be crushed, cut, or chewed.
  • Intravenous solutions should be administered over at least 2 hours (either peripheral or central vein); do not administer intravenous solution by rapid or bolus injection.
  • NEUPOGEN® is the trademark name for filgrastim, representing recombinant methionyl human granulocyte colony-stimulating factor (r-methHuG-CSF).
  • NEUPOGEN® is a 175 amino acid protein produced by recombinant DNA technology utilizing Escherichia coli ( E. coli ).
  • E. coli Escherichia coli
  • NEUPOGEN® has a molecular weight of 18,800 daltons and an amino acid sequence similar to that of natural human DNA except for the additional methionine at the N-terminal, necessary for expression in E. coli .
  • NEUPOGEN® may be administered as an IV or a subcutaneous infusion.
  • NEUPOGEN® be administered at least 24 hours after bone marrow infusion, with dosage modifications determined by neutrophil response. If necessary, NEUPOGEN® maybe diluted in 5% dextrose with the addition of Albumin(human) to prevent absorption to plastic materials. Dilution to final concentration less than 5 mcg/mL is not recommended at any time. Do not dilute with saline as the product may precipitate. When using either vials or prefilled syringes, do not save unused drugs for later administration. Dispose of all unused portions.
  • TBI Total Body Irradiation
  • TBI will be administered per standard of care procedure as implemented by radiation oncologists.
  • TBI alone for post-pubescent patients with dose/fractionation not exceeding 2 Gy ⁇ 6 is well within the tolerance of most normal organs for ⁇ 5% risk of severe late toxicity (organ failure or major dysfunction) by 5 years.
  • Notable exceptions are risks of cataract development, bone marrow suppression, and ovarian and testicular dysfunction.
  • the most common acute effects include nausea, vomiting, diarrhea, and painful swelling of the parotid glands.
  • TBI When TBI is given in conjunction with other therapies in the transplant setting, there is additional risk of side effects including loss of appetite, dry mouth, difficult or painful swallowing, headache, stomatitis (sore throat/mouth), altered skin integrity, hair loss, swelling, increased risk for infection and/or bleeding, possible lung failure, dry cough, fatigue, anxiety, fever, possible liver failure, lung scarring, loss of vision, shortness of breath, sterility, heartburn, cystitis, sleep disturbances, altered gastrointestinal and genitourinary function, neuropathy, fistulas, altered endocrine function, pericarditis, and increased risk of a second cancer.
  • the incidence of most major toxicity when radiation is given in conjunction with other therapy as outlined above is still low, rare, serious side effects are possible.
  • the expected outcome for the ABD study is that the incidence of acute GvHD will be no different from haploidentical transplant patients that receive post-transplant Cyclophosphamide without the supplemental ABD graft. This outcome is also expected for the EAGD patients while in addition we anticipate a lower incidence of infectious complications in the early post-transplant period (100 days) and a decreased incidence of relapsed disease (1, 2, and 5 years).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Zoology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biotechnology (AREA)
  • Cell Biology (AREA)
  • Organic Chemistry (AREA)
  • Hematology (AREA)
  • Wood Science & Technology (AREA)
  • Genetics & Genomics (AREA)
  • Developmental Biology & Embryology (AREA)
  • Virology (AREA)
  • General Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Transplantation (AREA)
  • Molecular Biology (AREA)
  • Emergency Medicine (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Materials For Medical Uses (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)
US15/754,973 2015-08-25 2016-08-25 Methods for stem cell transplantation Abandoned US20190183930A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US15/754,973 US20190183930A1 (en) 2015-08-25 2016-08-25 Methods for stem cell transplantation

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201562209721P 2015-08-25 2015-08-25
PCT/US2016/048738 WO2017035375A1 (en) 2015-08-25 2016-08-25 Methods for stem cell transplantation
US15/754,973 US20190183930A1 (en) 2015-08-25 2016-08-25 Methods for stem cell transplantation

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/048738 A-371-Of-International WO2017035375A1 (en) 2015-08-25 2016-08-25 Methods for stem cell transplantation

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US17/691,477 Continuation US20220265720A1 (en) 2015-08-25 2022-03-10 Methods for stem cell transplantation

Publications (1)

Publication Number Publication Date
US20190183930A1 true US20190183930A1 (en) 2019-06-20

Family

ID=58101080

Family Applications (2)

Application Number Title Priority Date Filing Date
US15/754,973 Abandoned US20190183930A1 (en) 2015-08-25 2016-08-25 Methods for stem cell transplantation
US17/691,477 Pending US20220265720A1 (en) 2015-08-25 2022-03-10 Methods for stem cell transplantation

Family Applications After (1)

Application Number Title Priority Date Filing Date
US17/691,477 Pending US20220265720A1 (en) 2015-08-25 2022-03-10 Methods for stem cell transplantation

Country Status (10)

Country Link
US (2) US20190183930A1 (he)
EP (2) EP4458953A3 (he)
JP (2) JP7105188B2 (he)
KR (2) KR20250048489A (he)
CN (2) CN115137752A (he)
AU (2) AU2016312610B2 (he)
CA (1) CA2996522A1 (he)
ES (1) ES2984387T3 (he)
IL (1) IL257678B2 (he)
WO (1) WO2017035375A1 (he)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190077868A1 (en) * 2016-03-14 2019-03-14 Millennium Pharmaceuticals, Inc. Methods of treating or preventing graft versus host disease
US11421005B2 (en) 2016-12-09 2022-08-23 The Uab Research Foundation Chimeric chlorotoxin receptors
US11447747B2 (en) 2018-02-08 2022-09-20 The Board Of Trustees Of The Leland Stanford Junior University Methods for allogenic hematopoietic stem cell transplantation
US12011461B2 (en) 2017-03-15 2024-06-18 Orca Biosystems, Inc. Compositions and methods of hematopoietic stem cell transplants

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4458953A3 (en) * 2015-08-25 2025-01-22 The UAB Research Foundation Methods for stem cell transplantation
BR112019026498A2 (pt) * 2017-06-14 2020-07-14 Adc Therapeutics Sa regimes de dosagem para a administração de um adc anti-cd25
EP3856206A1 (en) * 2018-09-27 2021-08-04 Phosphogam, Inc. Methods and compositions for the expansion and use of allogeneic gamma/delta-t cells
KR20200145328A (ko) 2019-06-21 2020-12-30 안혜빈 자동 물분사 칠판지우개

Family Cites Families (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69434968T2 (de) * 1993-05-17 2008-01-10 Yeda Research And Development Co., Ltd. Tiermodell für hepatitis-virus infektion
US7078034B2 (en) * 1999-01-28 2006-07-18 Palmetto Health Alliance In vitro activated γ δ lymphocytes
CA2360046A1 (en) * 1999-01-28 2000-08-03 Lawrence S. Lamb, Jr. In vitro activated gamma delta lymphocytes
AU2002322857A1 (en) * 2001-08-01 2003-02-17 Jewish Hospital Healthcare Services, Inc. Cellular compositions which facilitate engraftment of hematopoietic stem cells while minimizing the risk of gvhd
EP1790664A1 (en) * 2005-11-24 2007-05-30 Ganymed Pharmaceuticals AG Monoclonal antibodies against claudin-18 for treatment of cancer
US20120269774A1 (en) * 2006-09-21 2012-10-25 Medistem Laboratories, Inc Allogeneic stem cell transplants in non-conditioned recipients
KR20100127277A (ko) * 2008-03-15 2010-12-03 에스엠티. 쥐 알 도시 앤드 에스엠티. 케이 엠 메타 인스티튜드 오브 키드니디지즈 앤드 리서치 센트레 이식면역 관용을 유도하기 위한 줄기 세포 조성물
EP2593098A4 (en) * 2010-07-16 2014-02-05 Univ Johns Hopkins METHOD AND COMPOSITIONS FOR CANCER IMMUNOTHERAPY
JP5955871B2 (ja) * 2011-03-17 2016-07-20 ミルテニイ バイオテック ゲゼルシャフト ミット ベシュレンクテル ハフツング Ｔｃｒアルファ／ベータを枯渇させた細胞調製物
US9499788B2 (en) * 2011-05-19 2016-11-22 Instituto De Medicina Molecular Cell line of lymphocytes comprising gamma-delta T cells, composition and production method thereof
CN109453198A (zh) * 2011-06-09 2019-03-12 佛罗里达大学研究基金会有限公司 移植物抗宿主疾病的治疗或预防方法
EP2785743B1 (en) * 2011-12-01 2019-08-14 The Brigham and Women's Hospital, Inc. Anti-ceacam1 recombinant antibodies for cancer therapy
AU2012355989B2 (en) * 2011-12-22 2016-12-15 Yeda Research And Development Co. Ltd. A combination therapy for a stable and long term engraftment using specific protocols for T/B cell depletion
KR20160068960A (ko) * 2013-10-25 2016-06-15 보드 오브 리전츠, 더 유니버시티 오브 텍사스 시스템 면역요법을 위한 다클론성 감마 델타 t 세포
CN103834615A (zh) * 2014-03-27 2014-06-04 叶永清 一种适用于培养γδT细胞的无血清培养基
EP4458953A3 (en) * 2015-08-25 2025-01-22 The UAB Research Foundation Methods for stem cell transplantation
WO2018035413A1 (en) * 2016-08-18 2018-02-22 The Uab Research Foundation Compositions and methods for cancer immunotherapy

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190077868A1 (en) * 2016-03-14 2019-03-14 Millennium Pharmaceuticals, Inc. Methods of treating or preventing graft versus host disease
US11421005B2 (en) 2016-12-09 2022-08-23 The Uab Research Foundation Chimeric chlorotoxin receptors
US12011461B2 (en) 2017-03-15 2024-06-18 Orca Biosystems, Inc. Compositions and methods of hematopoietic stem cell transplants
US11447747B2 (en) 2018-02-08 2022-09-20 The Board Of Trustees Of The Leland Stanford Junior University Methods for allogenic hematopoietic stem cell transplantation
US11952588B2 (en) 2018-02-08 2024-04-09 The Board Of Trustees Of The Leland Stanford Junior University Methods for allogenic hematopoietic stem cell transplantation

Also Published As

Publication number Publication date
EP3340997B1 (en) 2024-02-14
US20220265720A1 (en) 2022-08-25
JP2022133453A (ja) 2022-09-13
ES2984387T3 (es) 2024-10-29
CA2996522A1 (en) 2017-03-02
AU2023202946A1 (en) 2023-06-01
EP3340997A1 (en) 2018-07-04
KR20180041229A (ko) 2018-04-23
NZ740901A (en) 2024-12-20
WO2017035375A1 (en) 2017-03-02
EP4458953A3 (en) 2025-01-22
IL257678B1 (he) 2023-12-01
JP2018525417A (ja) 2018-09-06
AU2016312610A1 (en) 2018-04-12
CN115137752A (zh) 2022-10-04
AU2016312610B2 (en) 2023-02-16
JP7105188B2 (ja) 2022-07-22
EP3340997A4 (en) 2019-03-06
IL257678B2 (he) 2024-04-01
CN108025023A (zh) 2018-05-11
KR20250048489A (ko) 2025-04-08
IL257678A (he) 2018-04-30
EP4458953A2 (en) 2024-11-06

Similar Documents

Publication Publication Date Title
US20220265720A1 (en) Methods for stem cell transplantation
Chang et al. Strategies for enhancing and preserving anti-leukemia effects without aggravating graft-versus-host disease
Morris et al. NKT cell–dependent leukemia eradication following stem cell mobilization with potent G-CSF analogs
Morris et al. Advances in the understanding of acute graft‐versus‐host disease
Bader et al. Rapid immune recovery and low TRM in haploidentical stem cell transplantation in children and adolescence using CD3/CD19-depleted stem cells
Serody et al. Comparison of granulocyte colony-stimulating factor (G-CSF)--mobilized peripheral blood progenitor cells and G-CSF--stimulated bone marrow as a source of stem cells in HLA-matched sibling transplantation
EP2663332B1 (en) Enhancement of allogeneic hematopoietic stem cell transplantation
Harper et al. Graft‐versus‐host disease
Song et al. Autologous stem cell transplantation for systemic lupus erythematosus: report of efficacy and safety at 7 years of follow-up in 17 patients
Lundqvist et al. Allogeneic hematopoietic cell transplantation as immunotherapy for solid tumors: current status and future directions
JP6802150B2 (ja) がん治療のための免疫療法
ES2660577T3 (es) Células que expresan características y propiedades citolíticas de Th1
Leung et al. Haematopoietic stem cell transplantation: current concepts and novel therapeutic strategies
Symons et al. The allogeneic effect revisited: exogenous help for endogenous, tumor-specific T cells
Ros-Soto et al. Allogeneic HSCT and Graft Versus Host Disease (GvHD): General Principles with Reference to Autoimmune Diseases
KR101694554B1 (ko) 자연살해세포 억제제 및 간엽줄기세포를 유효성분으로 포함하는 이식편대숙주질환의 예방 또는 치료를 위한 세포치료제 조성물
Fassas et al. Separating graft-versus-tumor from graft-versus-host reactions
WO2018153936A1 (en) Adipose tissue-derived mesenchymal stromal cells for use in the treatment of graft- versus-host disease
Greiner et al. Immunological and Clinical Impact of Manipulated and Unmanipulated DLI after Allogeneic Stem Cell
Ueno et al. Allogeneic peripheral blood progenitor cell transplantation in solid tumors
Stankevich et al. Experience of clinical mesenchymal stem cells (MSCs) usage for prophylaxis and GVHD treatment in patients undergoing allo-HSCT
Kolb et al. W Zhao, JJ Li, DY Cao et al.,“Intravenous injection of mesenchymal stem cells is effective in treating liver fibrosis" World Journal of Gastroenterology, vol. 18, no. 10, pp. 1048–1058
Fernandez et al. Gemtuzumab-ozogamicin (GO; Mylotarg®) as part of consolidation therapy for AML before autograft: Low incidence of hepatic veno-occlusive disease
Ferrara et al. Cellular Therapy for Hematology Malignancies: Allogeneic Hematopoietic Stem Transplantation, Graft-Versus-Host Disease, and Graft Versus Leukemia Effects
Lundqvist et al. Solid tumors in adults CHAPTER

Legal Events

Date Code Title Description
AS Assignment

Owner name: THE UAB RESEARCH FOUNDATION, ALABAMA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:SAAD, AYMAN;LAMB, LAWRENCE S;MINEISHI, SHIN;SIGNING DATES FROM 20180312 TO 20180402;REEL/FRAME:045460/0169

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: RESPONSE TO NON-FINAL OFFICE ACTION ENTERED AND FORWARDED TO EXAMINER

STPP Information on status: patent application and granting procedure in general

Free format text: FINAL REJECTION MAILED

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: FINAL REJECTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION