Compositions and methods for immunotherapy
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 one of a chimeric costimulatory receptor. Methods of using the immunoresponsive cell include those 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 chimeric antigen receptor (CAR) that binds to a first antigen with a dissociation constant (Kd) of about 5×10 −8 M or more, wherein binding of the CAR to the first antigen is capable of delivering an activation signal to the immunoresponsive cell, and
b) a chimeric co-stimulating receptor (CCR) that binds to a second antigen, wherein binding of the CCR to the second antigen is capable of delivering a costimulatory signal to the immunoresponsive cell but does not alone deliver an activation signal to the immunoresponsive cell,
wherein the immunoresponsive cell is capable of (i) exhibiting negligible cytolytic activity against cells that are single positive for the first antigen, and (ii) inducing cytolytic activity against cells that are positive for both the first antigen and second antigens.
2. 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), a regulatory T cell, a human embryonic stem cell, and a pluripotent stem cell from which lymphoid cells may be differentiated.
3. The immunoresponsive cell of claim 1 , wherein the first and/or second antigen is a tumor antigen or a pathogen antigen.
4. The immunoresponsive cell of claim 1 , wherein said CAR is recombinantly expressed.
5. The immunoresponsive cell of claim 1 , wherein the CAR is expressed from a vector.
6. The immunoresponsive cell of claim 1 , wherein the chimeric co-stimulating receptor (CCR) is expressed from a vector.
7. The immunoresponsive cell of claim 1 , wherein said immunoresponsive cell is autologous.
8. The immunoresponsive cell of claim 1 , wherein said first and second antigens are selected from the group consisting of CAIX, CEA, CD5, CD7, CD10, CD19, CD20, CD22, CD30, CD33, CD34, CD38, CD41, CD44, CD49f, CD56, CD74, CD133, CD138, a cytomegalovirus (CMV) infected cell antigen, EGP-2, EGP-40, EpCAM, erb-B2, erb-B3 erb-B4 FBP, Fetal acetylcholine receptor, folate receptor-a, GD2, GD3, HER-2, hTERT, IL-13R-a2, x-light chain, KDR, LeY, LI cell adhesion molecule, MAGE-AI, MUC1, Mesothelin, NKG2D ligands, NY-ESO-1, oncofetal antigen (h5T4), PSCA, PSMA, ROR1, TAG-72, VEGF-R2, and WT-1.
9. The immunoresponsive cell of claim 1 , wherein said first and second antigens are distinct antigens selected from the group consisting of CD133, a cytomegalovirus (CMV) infected cell antigen, erb-B2, KDR, Mesothelin, NKG2D ligands, NY-ESO-1, oncofetal antigen (h5T4), PSCA, PSMA, CD19, VEGF-R2, and WT-1.
10. The immunoresponsive cell of claim 1 , wherein said first and second antigens are selected from the group consisting of HER2, MUC1, CD44, CD49f, EpCAM, CEA, CD133, a cytomegalovirus (CMV) infected cell antigen, EGP-2, EGP-40, EpCAM, erb-B2, erb-B3, erb-B4, FBP, KDR, Mesothelin, NKG2D ligands, NY-ESO-1, oncofetal antigen (h5T4), PSCA, PSMA, VEGF-R2, and WT-1.
11. The immunoresponsive cell of claim 1 , wherein said first and second antigens are CD10 and CD19.
12. The immunoresponsive cell of claim 1 , wherein said first and second antigens are CD56 and CD138.
13. The immunoresponsive cell of claim 1 , wherein said first and second antigens are distinct antigens selected from the group consisting of mesothelin, folate receptor-a, CD44, and CD133.
14. The immunoresponsive cell of claim 1 , wherein the intracellular signaling domain of said CAR is a CD3-chain signaling domain.
15. The immunoresponsive cell of claim 1 , wherein the intracellular signaling domain of the chimeric co-stimulating receptor (CCR) is a CD97, CD11a-CD18, CD2, ICOS, CD27, CD154, CD5, OX40, 4-1BB or CD28 signaling domain.
16. The immunoresponsive cell of claim 1 , wherein the CAR is 19z1 or Pz1.
17. The immunoresponsive cell of claim 1 , wherein the immunoresponsive cell is a T cell.
18. A kit comprising an immunoresponsive cell comprising:
(a) a chimeric antigen receptor (CAR) that binds to a first antigen with a dissociation constant (Kd) of about 5×10 −8 M or more, wherein binding of the CAR to the first antigen is capable of delivering an activation signal to the immunoresponsive cell, and
(b) a chimeric co-stimulating receptor (CCR) that binds to a second antigen, wherein binding of the CCR to the second antigen is capable of delivering a costimulatory signal to the immunoresponsive cell but does not alone deliver an activation signal to the immunoresponsive cell,
wherein the immunoresponsive cell is capable of (i) exhibiting negligible cytolytic activity against cells that are single positive for the first antigen, and (ii) inducing cytolytic activity against cells that are positive for both the first antigen and second antigens.
19. The immunoresponsive cell of claim 1 , wherein the CAR binds to the first antigen with a dissociation constant (K d ) of about 1×10 −7 M or more.
20. The immunoresponsive cell of claim 1 , wherein the CAR binds to the first antigen with a dissociation constant (K d ) of about 1×10 −6 M or more.
21. The immunoresponsive cell of claim 1 , wherein the CAR binds to the first antigen with a binding affinity that is lower compared to the binding affinity with which the CCR binds to the second antigen.
22. The immunoresponsive cell of claim 1 , wherein said first antigen is PSCA.
23. The immunoresponsive cell of claim 1 , wherein said second antigen is PSMA.
24. A pharmaceutical composition comprising an immunoresponsive cell of any one of claims 1 - 3 , 4 - 16 , 17 and 19 - 23 and a pharmaceutically acceptable excipient.