Compositions and methods for immune cell modulation in adoptive immunotherapies

Patent metadata

Field	Value
Publication number	US-11413309-B2
Application number	US-201716071460-A
Country	US
Kind code	B2
Filing date	Jan 20, 2017
Priority date	Jan 20, 2016
Publication date	Aug 16, 2022
Grant date	Aug 16, 2022

Abstract

Compounds that either produced a higher proportion or greater absolute number of phenotypically identified nave, 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 method of modulating T cells, comprising contacting a population of T cells in vitro or ex vivo with a sufficient amount of a composition to obtain a population of modulated T cells, wherein the composition comprises (i) a mammalian target of rapamycin (mTOR) inhibitor, and (ii) dimethyl prostaglandin E2 (dmPGE2) or an analogue or derivative thereof,
wherein the modulated T cells exhibit (a) reduced expression of one or more T cell exhaustion markers, or (b) increased mitochondrial spare respiratory capacity, in comparison to a population of T cells that are not modulated with the composition, and
wherein the one or more T cell exhaustion markers include one or more of PD-1 and Tim-3.

2. The method of claim 1 , further comprising isolating one or more desired subpopulations from the modulated T cells.

3. The method of claim 2 , wherein the one or more desired subpopulations comprises naive T cells, stem cell memory T cells, and/or central memory T cells.

4. The method of claim 1 , wherein the T cells,
(a) 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;
(b) are isolated from
(i) a healthy subject;
(ii) a subject having an autoimmue disease, a hematopoietic malignancy, a virus infection or a solid tumor;
(iii) a subject previously administered with genetically modified immune cells; or
(iv) a subject that is CMV seropositive;

(c) are differentiated in vitro from stem cells, hematopoietic stem or progenitor cells, or progenitor cells; or
(d) are trans-differentiated in vitro from non-pluripotent cells of hematopoietic or non-hematopoietic lineage.

5. The method of claim 4 , wherein the T cells are differentiated in vitro from stem cells, hematopoietic stem or progenitor cells, or progenitor cells; wherein the stem cells, hematopoietic stem or progenitor cells, or progenitor cells comprise at least one genetic modification; and wherein the at least one genetic modification is retained in the T cells.

6. The method of claim 5 , wherein
(a) the at least one genetic modification comprises insertion or modification of a sequence encoding at least one of a safety switch protein, a targeting modality, a receptor, a signaling molecule, a transcription factor, a pharmaceutically active protein or peptide, a drug target candidate, or a protein promoting one or more activities; wherein the one or more activities comprise one or more of engraftment, trafficking, homing, viability, self-renewal, persistence, immune response regulation and modulation, and survival of the immune cells; or
(b) the at least one genetic modification comprises one or more of:
(i) deletion or reduced expression of B2M, TAP1, TAP2, Tapasin, NLRC5, PD1, LAG3, TIM3, RFXANK, CIITA, RFX5, RFXAP, or any gene in the chromosome 6p21 region; and
(ii) introduced or increased expression of HLA-E, 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.

7. The method of claim 5 , wherein the at least one genetic modification comprises an insertion, a deletion, or a nucleic acid replacement.

8. The method of claim 5 , wherein the at least one genetic modification comprises an exogenous nucleic acid encoding a T Cell Receptor (TCR) and/or a Chimeric Antigen Receptor (CAR).

9. The method of claim 4 , wherein the T cells are differentiated in vitro from stem cells; and wherein the stem cells comprise induced pluripotent stem cells (iPSCs) or embryonic stem cells (ESCs).

10. The method of claim 4 , wherein the T cells are differentiated in vitro from progenitor cells; and wherein the progenitor cells are CD34+ hemogenic endothelium cells, multipotent progenitor cells, or T cell progenitor cells.

11. The method of claim 1 , wherein the population of modulated T cells comprises at least one of the following:
(a) increased central memory T cell subpopulation; and
(b) decreased effector T cell subpopulation;
in comparison to a population of T cells that are not modulated with the composition.

12. The method of claim 11 , wherein the population of modulated T cells further comprises (a) increased gene expression in at least one of CD27, C—C chemokine receptor type 7 (CCR7), CD62L, transcription factor 7 (TCF7), lymphoid enhancer-binding factor 1 (LEF1), and (b) decreased gene expression in at least one of PR domain zinc finger protein 1 (BLIMP-1), fructose-bisphosphate aldolase C (ALDOC), gamma enolase (ENO2), PD-1 and Tim-3, in comparison to a population of T cells that are not modulated with the composition.

13. The method of claim 12 , wherein the population of modulated T cells comprises increased spare respiratory capacity (SRC) in comparison to a population of T cells that are not modulated with the composition.

14. The method of claim 12 , wherein the population of modulated T cells further comprises improved expansion and viability in comparison to a population of T cells that are not modulated with the composition.

15. The method of claim 12 , wherein the population of modulated T cells further comprises improved capability in tumor clearance and persistence in comparison to a population of T cells that are not modulated with the composition.

16. A composition comprising the modulated T cells made by claim 1 and a therapeutically acceptable medium.

17. The method of claim 1 , wherein:
(a) the mTOR inhibitor is rapamycin, sirolimus, temsirolimus, 40-O-(2-hydroxy)ethyl-rapamycin (everolimus), 40-O-(3-hydroxy)propyl-rapamycin, 40-O-(2-[2-hydroxy)ethoxy]ethyl-rapamycin, or 40-O-tetrazole-rapamycin; and
(b) the analogue or derivative of dmPGE2 is PGE 2 , 16,16-dimethyl PGE 2 p-(p-acetamidobenzamido) phenyl ester, 11-deoxy-16,16-dimethyl PGE 2 , 9-deoxy-9-methylene-16,16-dimethyl PGE 2 , 9-deoxy-9-methylene PGE 2 , 9-keto Fluprostenol, 5-trans PGE 2 , 17-phenyl-omega-trinor PGE 2 , PGE 2 serinol amide, PGE 2 methyl ester, 16-phenyl tetranor PGE 2 , 15(S)-15-methyl PGE 2 , 15(R)-15-methyl PGE 2 , 8-iso-15-keto PGE 2 , 8-iso PGE 2 isopropyl ester, 8-iso-16-cyclohexyl-tetranor PGE 2 , 20-hydroxy PGE 2 , 20-ethyl PGE 2 , 11-deoxy PGEi, nocloprost, sulprostone, butaprost, 15-keto PGE 2 , or 19 (R) hydroxy PGE 2 .

18. A composition comprising:
(a) an isolated population of modulated T cells;
(b) a mammalian target of rapamycin (mTOR) inhibitor; and
(c) dimethyl prostaglandin E2 (dmPGE2) or an analogue or derivative thereof,
wherein the modulated T cells exhibit (a) reduced expression of one or more T cell exhaustion markers, or (b) increased mitochondrial spare respiratory capacity, in comparison to a population of T cells that are not modulated with the composition, and
wherein the one or more T cell exhaustion markers include one or more of PD-1 and Tim-3.

19. The composition of claim 18 ,
(a) wherein the mTOR inhibitor is selected from rapamycin, and analogues and derivatives thereof;
(b) wherein the analogue or derivative of dmPGE2 is selected from the group consisting of PGE 2 , 16,16-dimethyl PGE 2 p-(p-acetamidobenzamido) phenyl ester, 11-deoxy-16,16-dimethyl PGE 2 , 9-deoxy-9-methylene-16, 16-dimethyl PGE 2 , 9-deoxy-9-methylene PGE 2 , 9-keto Fluprostenol, 5-trans PGE 2 , 17-phenyl-omega-trinor PGE 2 , PGE 2 serinol amide, PGE 2 methyl ester, 16-phenyl tetranor PGE 2 , 15(S)-15-methyl PGE 2 , 15(R)-15-methyl PGE 2 , 8-iso-15-keto PGE 2 , 8-iso PGE 2 i

Assignees

• Fate Therapeutics Inc

Inventors

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

Classifications

• A61K40/42

  Cancer antigens · CPC title

• A61K40/31

  Chimeric antigen receptors [CAR] · CPC title

• A61K40/11

  T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells · CPC title

• A61K2239/31

  characterized by the route of administration · CPC title

• A61K2239/38

  characterised by the dose, timing or administration schedule · CPC title