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CN-122029273-A - Compositions and methods for activating immune cells

CN122029273ACN 122029273 ACN122029273 ACN 122029273ACN-122029273-A

Abstract

The present application provides compositions and methods for producing Antigen Presenting Cells (APCs) from cancer cells (e.g., hematologic cancer cells) involving one or more agents selected from STAT3 activators (e.g., IL-10), IFNgamma receptor activators (e.g., IFNgamma), TNFalpha receptor activators (e.g., TNFalpha), IL-4 receptor activators (e.g., IL-4), GM-CSF receptor activators (e.g., GM-CSF), and/or IL-6 receptor activators (e.g., IL-6). Also provided are APCs produced thereby, and methods of activating immune cells (e.g., T cells) via co-culture with APCs. Activated immune cell compositions and methods of treatment involving activated immune cells are also provided.

Inventors

  • LIU YUAN
  • BIAN ZHEN
  • SHI LEI
  • H. Shi Daili

Assignees

  • MDX管理有限责任公司

Dates

Publication Date
20260512
Application Date
20240814
Priority Date
20230816

Claims (20)

  1. 1. A method of producing a population of antigen presenting cells ("HC-APCs") that present antigens associated with hematological cancers, comprising: Contacting blood cancer cells obtained from an individual having said blood cancer with one or more survival, differentiation and/or maturation factors ("S/D/M factors") comprising one or more agents selected from the group consisting of 1) STAT3 activator, 2) tnfα receptor (TNFR) activator, 3) interferon gamma (IFNGR) activator, and 4) interleukin-4 receptor (IL-4R) activator, thereby producing said HC-APC population.
  2. 2. A method of producing an activated immune cell comprising: a) Generating a population of HC-APCs according to the method of claim 1, and B) Contacting the HC-APC with an immune cell, thereby producing an activated immune cell.
  3. 3. A method of producing activated immune cells comprising contacting immune cells with a population of antigen presenting cells ("HC-APCs") presenting antigens associated with hematological cancers, thereby producing activated immune cells, wherein the HC-APCs are derived from hematological cancer cells after having been contacted with one or more survival, differentiation and/or maturation factors ("S/D/M factors") comprising one or more agents selected from the group consisting of 1) STAT3 activators, 2) TNFa receptor (TNFR) activators, 3) interferon gamma (IFNGR) activators, and 4) interleukin-4 receptor (IL-4R) activators.
  4. 4. The method of any one of claims 1 to 3, wherein the STAT3 activator is selected from the group consisting of IL-10, IL-10 family members, IL-10R agonist antibodies, IL-10 family cytokine receptor agonist antibodies, small molecule activators of IL-10R and small molecule activators of STAT3, optionally wherein the STAT3 activator is selected from the group consisting of IL-10 family cytokines, IL-12 family cytokines, IL-6 family cytokines, small molecule STAT3 activators and G-CSF.
  5. 5. The method of claim 4, wherein the STAT3 activator is selected from the group consisting of IL-10, IL-22, IL-19, IL-20, IL-24, IL-12, IL-23, IL-6, coloravin TFA, galvanic D, G-CSF, IL-7, IL-9, IL-15, and IL-21, optionally wherein the STAT3 activator is selected from the group consisting of IL-10, IL-22, IL-19, IL-20, IL-24, IL-12, IL-23, coloravin TFA, and Galvanic D.
  6. 6. The method of any one of claims 1 to 5, wherein one or more of the S/D/M factors comprises an interleukin-4 receptor (IL-4R) activator, optionally wherein the IL-4R activator is selected from the group consisting of IL-4, an IL-4R agonist antibody, and a small molecule activator of IL-4R.
  7. 7. The method of claim 6, wherein the IL-4R activator is IL-4.
  8. 8. The method of any one of claims 1 to 7, wherein one or more of the S/D/M factors comprises a TNFR activator, optionally wherein the TNFR activator is selected from the group consisting of TNFa, TNFR agonist antibodies, and small molecule activators of TNFR.
  9. 9. The method of claim 8, wherein the TNFR activator is tnfa.
  10. 10. The method of any one of claims 1 to 9, wherein one or more of the S/D/M factors comprises an IFNGR activator, optionally wherein the IFNGR activator is selected from the group consisting of IFNγ, IFNGR agonist antibodies, and small molecule activators of IFNGR.
  11. 11. The method of claim 10, wherein the IFNGR activator is ifnγ.
  12. 12. The method of any one of claims 1-11, wherein one or more of the S/D/M factors are present in a single composition.
  13. 13. The method of any one of claims 1 to 12, wherein one or more of the S/D/M factors comprises two or more agents selected from the group consisting of 1) STAT3 activator, 2) TNFR activator, 3) IFNGR activator, and 4) IL-4R activator.
  14. 14. The method of any one of claims 1 to 13, wherein one or more of the S/D/M factors comprises three or more agents selected from the group consisting of 1) STAT3 activator, 2) TNFR activator, 3) IFNGR activator, and 4) IL-4R activator.
  15. 15. The method of claim 14, wherein one or more of the S/D/M factors comprises 1) a STAT3 activator, 2) a TNFR activator, and 3) an IFNGR activator, optionally wherein one or more of the S/D/M factors comprises an IL-10 family cytokine, TNFa, and IFNγ.
  16. 16. The method of claim 15, wherein one or more of the S/D/M factors comprises 1) a STAT3 activator, 2) a TNFR activator, 3) an IFNGR activator, and 4) an IL-4R activator, optionally wherein one or more of the S/D/M factors comprises an IL-10 family cytokine, TNFa, IL-4, and IFNy.
  17. 17. The method of any one of claims 1 to 16, wherein one or more of the S/D/M factors further comprises an IL-6 receptor (IL-6R) activator and/or a GM-CSF receptor (GM-CSFR) activator, optionally wherein the IL-6R activator is selected from the group consisting of IL-6, IL-6R agonist antibodies, and small molecule activators of IL-6R, and optionally wherein the GM-CSFR activator is selected from the group consisting of GM-CSF, GM-CSFR agonist antibodies, and small molecule activators of GM-CSFR.
  18. 18. The method of claim 17, wherein the IL-6R activator is IL-6, and wherein the GM-CSFR activator is GM-CSF.
  19. 19. The method of any one of claims 1 to 18, wherein the blood cancer cells are contained in a cell mixture comprising monocytes from the individual.
  20. 20. The method of any one of claims 1 to 19, wherein prior to contacting the HC-APC with an immune cell, the method further comprises contacting the HC-APC with one or more optimisation factors selected from the group consisting of type I interferon, ifnγ, tnfα, TLR ligand, CD40L or CD40 linked antibody, anti-PD-L1 antibody and TPI-1; Optionally wherein the type I interferon comprises IFN alpha and/or IFN beta; optionally wherein the TLR ligand is selected from the group consisting of R848, poly IC, cpG, or LPS, and Further optionally wherein the TLR ligand comprises R848 and a poly IC.

Description

Compositions and methods for activating immune cells Cross Reference to Related Applications The application claims the benefit and priority of U.S. provisional application No. 63/519,974 filed on 8/16 of 2023, the contents of which are incorporated herein by reference in their entirety. Technical Field The present invention relates to compositions and methods for a) promoting differentiation and/or maturation of Antigen Presenting Cells (APCs) derived from cancer cells, such as malignant myeloid cells or B-lymphoblastic/lymphocytes from cancer patients, and B) activating immune cells, such as T cells. Background Hematological malignancies (also known as hematological cancers) are the fifth most common cancer group, with diseases including acute and chronic lymphoblastic leukemia (ALL and CLL), acute and chronic myelogenous leukemia (AML and CML), myelodysplastic syndrome (MDS), hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple Myeloma (MM), and the like. Among the different types of blood cancers, non-hodgkin lymphoma (NHL) is the most common disease (> 40%), followed by leukemia (31%), then MM (18%). Characterization of cell types showed that B cell lineage malignancies such as B-ALL, CLL, NHL and MM account for >50% of all cases, and the remainder were predominantly myeloid leukemia (AML and CML). Malignant cells are generally represented in peripheral blood (leukemia), bone marrow (leukemia and MM), lymph nodes (lymphoma) and spleen, as well as diffuse areas such as brain, spinal cord and abdominal cavity, depending on where the cancer originates. Traditionally, the treatment of hematological malignancies has included mainly chemotherapy, radiation therapy, and Hematopoietic Stem Cell Transplantation (HSCT). However, with advances in tumor immunology, immune-targeted therapies such as monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, and chimeric antigen receptor T (CAR-T) cell therapies have opened new approaches for the treatment of these malignancies. In particular, CAR-T cell therapy has revolutionized the treatment of hematological malignancies and achieved unprecedented responses in recent years. However, rapid commercialization of CAR-T cell therapies poses significant challenges for their management, such as managing the toxicity associated with CAR-T therapies and patient relapse after receiving CAR T cell therapies. See, for example, front immunol 2022; 13: 927153. The disclosures of all publications, patents, patent applications, and published patent applications mentioned herein are incorporated by reference in their entirety. Disclosure of Invention In one aspect, the application provides a method of producing a population of antigen presenting cells ("APCs") ("HC-APCs") that present antigens associated with hematological cancers, comprising contacting hematological cancer cells obtained from an individual having hematological cancer with one or more survival, differentiation and/or maturation factors ("S/D/M factors") comprising one or more agents selected from the group consisting of 1) STAT3 activators, 2) TNFa receptor (TNFR) activators, 3) interleukin 4 receptor (IL-4R) activators, and 4) interferon gamma (IFNGR) activators, thereby producing a population of HC-APCs. In another aspect, the application provides a method of producing an activated immune cell comprising a) producing a population of antigen presenting cells ("APCs") ("HC-APCs") presenting antigens associated with hematological cancer according to the method described above, and b) contacting the HC-APCs with the immune cell, thereby producing the activated immune cell. In another aspect, the application provides a method of producing activated immune cells comprising contacting immune cells with a population of antigen presenting cells ("HC-APCs") that present antigens associated with hematological cancers, thereby producing activated immune cells, wherein the HC-APCs are derived from hematological cancer cells after having been contacted with one or more survival, differentiation and/or maturation factors ("S/D/M factors") comprising one or more agents selected from the group consisting of 1) STAT3 activators, 2) TNFa receptor (TNFR) activators, 3) interleukin 4 (IL-4R) activators, and 4) interferon gamma (IFNGR) activators. In some embodiments according to any of the methods described above, the STAT3 activator is selected from the group consisting of a small molecule STAT3 activator, IL-10, an IL-10 family member, an IL-10R agonist antibody, an IL-10 family cytokine receptor agonist antibody, and a small molecule activator of IL-10R. In some embodiments, the STAT3 activator is selected from the group consisting of an IL-10 family cytokine, an IL-12 family cytokine, an IL-6 family cytokine, an IL-7 family cytokine, an IL-9 family cytokine, an IL-15 family cytokine, an IL-21 family cytokine, and G-CSF. In some embodiments, the STAT3 activator is selected from the group consisting of IL-10, IL-22,