Method and compositions for cellular immunotherapy
The present invention provides methods and compositions to confer and/or augment immune responses mediated by cellular immunotherapy, such as by adoptively transferring genetically modified tumor specific CD8+ T cells in the presence of tumor-specific, subset specific genetically modified CD4+ T cells, wherein the CD4+ T cells confer and/or augment a CD8+ T cells ability to sustain anti-tumor reactivity and increase and/or maximize tumor-specific proliferation of the tumor-specific CD8+ T cells of interest. Pharmaceutical formulations produced by the method, and methods of using the same, are also described.
1. An adoptive cellular immunotherapy composition comprising chimeric antigen receptor-modified CD4 + T lymphocytes and chimeric antigen receptor-modified CD8 + T lymphocytes, wherein:
(a) the chimeric antigen receptor-modified CD4+ T lymphocytes in the composition consist of helper T lymphocytes that contain a chimeric antigen receptor that specifically binds to an antigen, wherein the CD4+ helper T lymphocytes are derived from: (i) a CD45RA+ CD62L+ naïve T cell enriched CD4+ population; or (ii) a CD45RA+ CD62L+ naïve T cell enriched and CD45RO+ CD62L+ central memory T cell enriched CD4+ population;
(b) the chimeric antigen receptor-modified CD8+ T lymphocytes in the composition consist of CD8+ cytotoxic T lymphocytes that are derived from a central memory-enriched CD8+ cell population and contain a chimeric antigen receptor that specifically binds to the antigen; and
wherein (a) at least 60% of the chimeric antigen receptor-modified CD4+ T lymphocytes are surface positive for CD62L and CD45RA or CD45RO; or (b) at least 80% of the chimeric antigen receptor-modified CD4+ T lymphocytes are surface positive for CD62L and CD45RA or CD45RO.
2. The adoptive cellular immunotherapy composition according to claim 1 , wherein the antigen is associated with a disease or disorder selected from a solid tumor, a hematologic malignancy, a melanoma, and an infection with a pathogen.
3. The adoptive cellular immunotherapy composition according to claim 1 , wherein the antigen is selected from ROR1, tEGFR, Her2, L1-CAM, CD19, CD20, CD22, mesothelin, and CEA.
4. The adoptive cellular immunotherapy composition according to claim 1 , wherein the antigen is a pathogen specific cell surface antigen selected from an HIV antigen, an HCV antigen, an HBV antigen, a hepatitis B surface antigen, a CMV antigen, and a parasitic antigen.
5. The adoptive cellular immunotherapy composition according to claim 1 , wherein the chimeric antigen receptor of (a) and/or (b) comprises an extracellular antibody variable domain or single-chain antibody fragment specific for an antigen associated with a disease or disorder, and an intracellular signaling module.
6. The adoptive cellular immunotherapy composition according to claim 5 , wherein each of the intracellular signaling module of the chimeric antigen receptor contained by the CD4+ T lymphocytes and the intracellular signaling module of the chimeric antigen receptor contained by the CD8+ T lymphocytes, individually, comprise (a) a CD28 costimulatory domain and a CD3 intracellular signaling domain, or (b) a 4-1BB costimulatory domain and a CD3 intracellular signaling domain.
7. The adoptive cellular immunotherapy composition according to claim 1 , wherein (a) the intracellular signaling domain of the chimeric antigen receptor contained by the CD8+ T lymphocytes is the same as the intracellular signaling domain of the chimeric antigen receptor contained by the CD4+ T lymphocytes, or (b) the chimeric antigen receptor contained by the CD8+ T lymphocytes is the same as the chimeric antigen receptor contained by the CD4+ T lymphocytes.
8. The adoptive cellular immunotherapy composition according to claim 1 , wherein (a) the intracellular signaling domain of the chimeric antigen receptor in the CD8+ T lymphocytes is different from the intracellular signaling domain of the chimeric antigen receptor in the CD4+ T lymphocytes; or (b) the chimeric antigen receptor contained by the CD8+ T lymphocytes is different than the chimeric antigen receptor contained by the CD4+ T lymphocytes.
9. The adoptive cellular immunotherapy composition according to claim 1 , wherein the CD4+ helper T lymphocytes are derived from a CD45RA+ CD62L+ naïve T cell-enriched CD4+ population.
10. The adoptive cellular immunotherapy composition according to claim 1 , wherein the CD4+ helper T lymphocytes are derived from a CD45RA+ CD62L+ naïve T cell-enriched and CD45RO+ CD62L+ central memory T cell-enriched CD4+ population.
11. The adoptive cellular immunotherapy composition according to claim 9 , wherein the CD4+ helper T lymphocytes augment the effector function of the CD8+ T lymphocytes.