Compositions and methods for immune cell modulation in adoptive immunotherapies

Patent metadata

Field	Value
Publication number	US-2025215396-A1
Application number	US-202519085376-A
Country	US
Kind code	A1
Filing date	Mar 20, 2025
Priority date	Jan 20, 2016
Publication date	Jul 3, 2025
Grant date	—

Abstract

Compounds that either produced a higher proportion or greater absolute number of phenotypically identified naïve, stem cell memory, central memory T cells, adaptive NK cells, and type I NKT cells are identified. Compositions and methods for modulating immune cells including T, NK, and NKT cells for adoptive cell therapies with improved efficacy are provided.

First claim

What is claimed is:

1 . A composition comprising a population of immune cells, and one or more agents selected from the group consisting of the compounds listed in Table 1, and derivatives and analogues thereof, wherein the one or more agents improves therapeutic potential of immune cells via modulating the immune cells.

2 . The composition of claim 1 , wherein the one or more agents
(a) improves cell expansion, maintenance, differentiation, dedifferentiation, and/or survival rate; (b) improves cell proliferation, cytotoxicity, persistence, cytokine response and secretion, and/or cell recall; and/or (c) increases the number or ratio of a desired immune cell subpopulation, upon modulating the immune cells with the one or more agents.

3 . The composition of claim 1 , wherein the immune cells comprise T cells, NKT cells, and/or NK cells.

4 . The composition of claim 3 , wherein the NK cells comprise (i) CD57−NK cells; or (ii) CD57− NKG2C+ NK cells.

5 . The composition of claim 2 , wherein the desired subpopulation of immune cells having increased number or ratio comprise
(a) naïve T cells, stem cell memory T cells, and/or central memory T cells; (b) type I NKT cells; or (c) CD57+ NK cells.

6 . The composition of claim 5 , wherein the CD57+ NK cells comprise adaptive NK cells.

7 . The composition of claim 6 , wherein the adaptive NK cells comprise CD57+ and at least one of NKG2C+, low PLZF, low SYK, low FcεRγ, low EAT-2, low TIGIT, low PD1, low CD7, low CD161, high LILRB1, high CD45RO, and low CD45RA.

8 . The composition of claim 1 , wherein the immune cells are isolated from or comprised in peripheral blood, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, or tumors.

9 . The composition of claim 1 , wherein the immune cells are isolated from
(a) a healthy subject; (b) a subject having an autoimmune disease, a hematopoietic malignancy, a virus infection or a solid tumor; (c) a subject previously administered with genetically modified immune cells; or (d) a subject that is CMV seropositive.

10 . The composition of claim 8 or 9 , wherein the isolated immune cells
(a) are genomically engineered and comprise an insertion, a deletion, or a nucleic acid replacement; or (b) comprise at least one genetically modified modality.

11 . The composition of claim 1 , wherein the immune cells
(a) are differentiated in vitro from stem cells, hematopoietic stem or progenitor cells, or progenitor cells; or (b) are trans-differentiated in vitro from non-pluripotent cells of hematopoietic or non-hematopoietic lineage.

12 . The composition of claim 11 , wherein the stem cells comprise induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs).

13 . The composition of claim 11 , wherein the progenitor cell is a CD34+ hemogenic endothelium cell, a multipotent progenitor cell, a T cell progenitor cell, a NK progenitor cell, or a NKT progenitor cell.

14 . The composition of claim 11 , wherein the stem cell, hematopoietic stem or progenitor cell, or progenitor cell
(a) is genomically engineered and comprises an insertion, a deletion, or a nucleic acid replacement, or (b) comprises at least one genetically modified modality.

15 . The composition of claim 1 , wherein the composition comprises one or more of a GSK3 inhibitor, a TGFβ receptor inhibitor, a ROCK inhibitor, a MEK inhibitor, a PDK1 agonist, and rapamycin.

16 . The composition of claim 15 , wherein the composition comprises a GSK3 inhibitor.

17 . The composition of claim 1 or 15 , wherein the composition further comprises one or more additives selected from the group consisting of peptides, antibodies, antibody fragments, cytokines, mitogens, growth factors, small RNAs, dsRNA, mononuclear blood cells, feeder cells, feeder cell components or replacement factors, vectors comprising one or more polynucleic acids of interest, chemotherapeutic agents or radioactive moieties, and immunomodulatory drugs (IMiDs).

18 . The composition of claim 17 , wherein the additive comprises at least one of stimulating cytokines comprising IL2, IL15, IL12, IL18 and IL21.

19 . The composition of claim 17 , wherein the additive comprises one or more of a MEK inhibitor, rapamycin, and a STING agonist.

20 . The composition of claim 2 , wherein the desired subpopulation of immune cells comprises immune cells having at least one genetically modified modality.

21 . The composition of claim 5 , wherein the desired subpopulation of immune cells comprises CD57+ NK cells having at least one genetically modified modality.

22 . The composition of claim 10, 14, 20 or 21 , wherein the genetically modified modality comprises at least one of safety switch proteins, targeting modalities, receptors, signaling molecules, transcription factors, pharmaceutically active proteins and peptides, drug target candidates; or proteins promoting engraftment, trafficking, homing, viability, self-renewal, persistence, immune response regulation and modulation, and/or survival of the immune cells.

23 . The composition of claim 22 , wherein the genetically modified modalities comprise one or more of (i) deletion or reduced expression of B2M, TAP1, TAP2, Tapasin, NLRC5, PD1, LAG3, TIM3, RFXANK, CIITA, RFX5, or RFXAP, and any gene in the chromosome 6p21 region; and (ii) introduced or increased expression of HLA-E, HLA-G, HACD16, hnCD16, 41BBL, CD3, CD4, CD8, CD47, CD113, CD131, CD137, CD80, PDL1, A2AR, Fc receptor, or surface triggering receptors for coupling with bi- or multi-specific or universal engagers.

24 . The composition of claim 21 , wherein the CD57+ NK cells comprise expression of hnCD16.

25 . The composition of claim 21 or 24 , wherein the CD57+ NK cells further comprise at least one of NKG2C+, low PLZF, low SYK, low FcεRγ, low EAT-2, low TIGIT, low PD1, low CD7, low CD161, high LILRB1, high CD45RO, and low CD45RA.

26 . The composition of claim 1 , comprising
(a) a population of NK cells, and a GSK3 inhibitor; (b) a population of NK cells, a GSK3 inhibitor, and IL15; or (c) a population of NK cells, a GSK3 inhibitor, IL15, and a STING agonist.

27 . A composition for improving therapeutic potential of immune cells suitable for adoptive cell-based therapies, comprising one or more agents selected from the group consisting of compounds listed in Table 1, and derivatives and analogues thereof, wherein the one or more agents improves therapeutic potential of immune cells thereof via modulating the immune cells.

28 . The composition of claim 27 , wherein the agent
(a) modulates cell expansion, maintenance and/or differentiation, (b) improves cell proliferation, cytotoxicity, cytokine response and secretion, recall, and/or persistence; (c) improves cell survival rate; and/or (d) increases the ratio of one or more desired cell subpopulation, of the immune cells.

29 . The composition of claim 27 or 28 , wherein the immune cells comprise T cells, NKT cells, and/or NK cells.

30 . The composition of claim 29 , wherein the NK cells comprise (i) CD57−NK cells; or (ii) CD57− NKG2C+ NK cells.

31 . The composition of claim 28 , wherein the one or more desired cell subpopulations with an increased ratio comprises:
(a) naïve T cells, stem cel

Assignees

• Fate Therapeutics Inc

Inventors

• Rosen Jonathan
• Rezner Betsy
• Valamehr Bahram
• Bjordahl Ryan
• Peralta Eigen

Classifications

• A61K38/2086

  IL-13 to IL-16 · CPC title

• A61K31/436

  the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title