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 receptor that binds an antigen and an exogenous co-stimulatory ligand, wherein the exogenous co-stimulatory ligand is 4-1BBL and/or CD80 or CD86.
2. The immunoresponsive cell of claim 1 , wherein the co-stimulatory ligand is constitutively or inducibly expressed.
3. The immunoresponsive cell of claim 1 , wherein at least two co-stimulatory ligands are constitutively expressed.
4. The immunoresponsive cell of claim 1 , wherein the cell is selected from the group consisting of a T cell, a Natural Killer (NK) cell, a cytotoxic T lymphocyte (CTL), and a regulatory T cell.
5. The immunoresponsive cell of claim 1 , wherein the antigen is a tumor or pathogen antigen.
6. The immunoresponsive cell of claim 3 , wherein the antigen is selected from the group consisting of prostate-specific membrane antigen (PSMA), Carcinoembryonic Antigen (CEA), IL13Ralpha, her-2, CD19, NY-ESO-1, HIV-1 Gag, Lewis Y, Mart-1, gp100, tyrosinase, WT-1, hTERT, and mesothelin.
7. The immunoresponsive cell of claim 1 , wherein the cell expresses a recombinant or an endogenous antigen receptor that is Pz1 or P28z.
8. The immunoresponsive cell of claim 1 , wherein the co-stimulatory ligand is a tumor necrosis factor (TNF) family ligand or an immunoglobulin (Ig) superfamily ligand.
9. The immunoresponsive cell of claim 8 , wherein the TNF family ligand is 4-1BBL.
10. The immunoresponsive cell of claim 8 , wherein the Ig superfamily ligand is selected from the group consisting of CD80 and CD86.
11. The immunoresponsive cell of claim 1 , wherein the immunoresponsive cell expresses 4-1BBL.
12. The immunoresponsive cell of claim 1 , wherein the immunoresponsive cell expresses 4-1BBL and CD80.
13. The immunoresponsive cell of claim 1 , wherein an endogenous or recombinant antigen receptor or antigen presenting complex is constitutively expressed on the surface of the T cell.
14. The immunoresponsive cell of claim 1 , wherein the co-stimulatory ligand is constitutively expressed on the surface of the T cell.
15. An immunoresponsive cell comprising a receptor that binds an antigen and an exogenous co-stimulatory ligand, wherein the co-stimulatory ligand is expressed in a retroviral vector.
16. A virus specific T cell expressing a vector encoding a polypeptide selected from the group consisting of CD80 and 4-1BBL.
17. The virus specific T cell of claim 16 , wherein the T cell recognizes a virus selected from the group consisting of Cytomegalovirus (CMV), Epstein Barr Virus (EBV), Human Immunodeficiency Virus (HIV), and influenza virus antigens.
18. A tumor antigen-specific T cell expressing a vector encoding a polypeptide selected from the group consisting of CD80 and 4-1BBL.
19. The tumor antigen-specific T cell of claim 18 , wherein the cell expresses CD80 and 4-1BBL.
20. The tumor antigen-specific T cell of claim 18 , wherein the vector is a retroviral vector.
21. The immunoresponsive cell of claim 15 , wherein the immunoresponsive cell expresses 4-1BBL and/or CD80 or CD86.
22. The immunoresponsive cell of claim 15 , wherein the co-stimulatory ligand is constitutively or inducibly expressed.
23. The immunoresponsive cell of claim 15 , wherein at least two co-stimulatory ligands are constitutively expressed.
24. The immunoresponsive cell of claim 1 , wherein the cell is selected from the group consisting of a T cell, a Natural Killer (NK) cell, a cytotoxic T lymphocyte (CTL), and a regulatory T cell.
25. The immunoresponsive cell of claim 15 , wherein the antigen is a tumor or pathogen antigen.
26. The immunoresponsive cell of claim 25 , wherein the antigen is selected from the group consisting of prostate-specific membrane antigen (PSMA), Carcinoembryonic Antigen (CEA), IL13Ralpha, her-2, CD19, NY-ESO-1, HIV-1 Gag, Lewis Y, Mart-1, gp100, tyrosinase, WT-1, hTERT, and mesothelin.
27. The immunoresponsive cell of claim 15 , wherein the cell expresses a recombinant or an endogenous antigen receptor that is Pz1 or P28z.
28. The immunoresponsive cell of claim 15 , wherein the co-stimulatory ligand is a tumor necrosis factor (TNF) family ligand or an immunoglobulin (Ig) superfamily ligand.
29. The immunoresponsive cell of claim 28 , wherein the TNF family ligand is 4-1BBL.
30. The immunoresponsive cell of claim 21 , wherein the immunoresponsive cell expresses CD80.
31. The immunoresponsive cell of claim 21 , wherein the immunoresponsive cell expresses CD86.
32. The immunoresponsive cell of claim 21 , wherein the immunoresponsive cell expresses 4-1BBL.
33. The immunoresponsive cell of claim 21 , wherein the immunoresponsive cell expresses 4-1BBL and CD80.
34. The immunoresponsive cell of claim 15 , wherein an endogenous or recombinant antigen receptor or antigen presenting complex is constitutively expressed on the surface of the T cell.
35. The immunoresponsive cell of claim 15 , wherein the co-stimulatory ligand is constitutively expressed on the surface of the T cell.
36. An immunoresponsive cell comprising a receptor that binds an antigen and an exogenous co-stimulatory ligand, wherein the immunoresponsive cell is a T-cell or NK cell and expresses 4-1BBL and/or CD80 or CD86.