Constitutive expression of costimulatory ligands on adoptively transferred T lymphocytes
The present invention provides immunoresponsive cells, including T cells, cytotoxic T cells, regulatory T cells, and Natural Killer (NK) cells, expressing at least one of an antigen-recognizing receptor and a co-stimulatory ligand and methods of use therefore for the treatment of neoplasia and other pathologies where an increase in an antigen-specific immune response is desired.
1. An immunoresponsive cell comprising:
a) a receptor that binds to an antigen, and
b) a nucleic acid encoding a recombinant co-stimulatory ligand, wherein the co-stimulatory ligand is a heterologously expressed cytokine, wherein the cytokine is selected from the group consisting of an IL-2, an IL-12 and an IL-21, and wherein the receptor is selected from a group consisting of a chimeric antigen receptor (CAR) and a T cell receptor (TCR).
2. The immunoresponsive cell of claim 1 , wherein the cell is a T cell.
3. The immunoresponsive cell of claim 1 , wherein the cytokine is an IL-12.
4. The immunoresponsive cell of claim 2 , wherein the cell comprises a cytotoxic T lymphocyte.
5. The immunoresponsive cell of claim 1 , wherein the nucleic acid is comprised on a vector.
6. The immunoresponsive cell of claim 5 , wherein the vector is a viral vector.
7. The immunoresponsive cell of claim 6 , wherein the vector is a retroviral vector.
8. The immunoresponsive cell of claim 7 , wherein the retroviral vector is a gamma-retroviral vector or a lentiviral vector.
9. The immunoresponsive cell of claim 1 , wherein the antigen is a tumor antigen.
10. The immunoresponsive cell of claim 9 , wherein the tumor antigen is expressed by a solid tumor.
11. The immunoresponsive cell of claim 10 , wherein the solid tumor is selected from the group consisting of prostate cancer, colon cancer, breast cancer, ovarian cancer, and glioblastoma.
12. The immunoresponsive cell of claim 9 , wherein the tumor antigen is selected from the group consisting of prostate-specific membrane antigen (PSMA), Carcinoembryonic Antigen (CEA), IL13Rα, Her-2, CD19, NY-ESO-1, Lewis Y, Mart-1, gp100, tyrosinase, WT-1, hTERT, and mesothelin.
13. The immunoresponsive cell of claim 9 , wherein the tumor antigen is expressed by a tumor expressing prostate-specific membrane antigen (PSMA), Carcinoembryonic Antigen (CEA), IL13Rα, Her-2, CD19, NY-ESO-1, Lewis Y, Mart-1, gp100, tyrosinase, WT-1, hTERT, or mesothelin.
14. The immunoresponsive cell of claim 1 , wherein the receptor is a chimeric antigen receptor (CAR).
15. The immunoresponsive cell of claim 14 , wherein the CAR comprises a ζ chain signaling domain.
16. The immunoresponsive cell of claim 14 , wherein the CAR further comprises a domain that provides a costimulatory signal.
17. The immunoresponsive cell of claim 14 , wherein the CAR comprises a CD28 signaling element.
18. The immunoresponsive cell of claim 17 , wherein the CAR is P28z.
19. The immunoresponsive cell of claim 1 , wherein the immunoresponsive cell is a T cell, the cytokine comprises an IL-12, and the antigen is expressed by a solid tumor selected from the group consisting of prostate cancer, colon cancer, breast cancer, ovarian cancer, and glioblastoma.
20. The immunoresponsive cell of claim 19 , wherein the receptor is a CAR.
21. A pharmaceutical composition comprising an effective amount of the immunoresponsive cell of claim 1 and a pharmaceutically acceptable carrier or excipient.
22. A pharmaceutical composition comprising an effective amount of the T cell of claim 2 and a pharmaceutically acceptable carrier or excipient.
23. A pharmaceutical composition comprising an effective amount of the T cell of claim 19 and a pharmaceutically acceptable carrier or excipient.
24. A kit comprising the immunoresponsive cell of claim 1 and instructions for administering the cell to a subject having or at risk of developing a neoplasia.
25. The kit of claim 24 , wherein the neoplasia is a solid tumor.
26. The kit of claim 25 , wherein the solid tumor is selected from the group consisting of prostate cancer, colon cancer, breast cancer, ovarian cancer, and glioblastoma.