Use of the CD2 signaling domain in second-generation chimeric antigen receptors
The present invention provides compositions and methods for treating cancer in a human. The invention includes relates to administering a genetically modified T cell expressing a CAR having an antigen binding domain, a transmembrane domain, a CD2 signaling domain, and a CD3 zeta signaling domain. The invention also includes incorporating CD2 into the CAR to alter the cytokine production of CAR-T cells in both negative and positive directions.
1. A method of treating a human with cancer, the method comprising:
administering to the human a T cell genetically engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises:
(i) an antigen binding domain, wherein the antigen binding domain targets a tumor antigen selected from the group consisting of CD19, CD20, CD22, ROR1, mesothelin, CD33, IL3Ra, c-Met, PSMA, Glycolipid F77, EGFRvIII, GD-2, NY-ESO-1 TCR, MAGE A3 TCR, and MUC1 (CA15-3), and any combination thereof,
(ii) a transmembrane domain,
(iii) a costimulatory signaling region comprising a CD2 signaling domain and a CD28 signaling domain, or a CD2 signaling domain and a 4-1BB signaling domain, wherein the CD2 signaling domain is encoded by a nucleic acid sequence comprising nucleotides 996-1346 of SEQ ID NO: 1, and
(iv) a CD3 zeta signaling domain,
thereby treating the human.
2. The method of claim 1 , wherein the T cell is an autologous T cell.
3. The method of claim 1 , wherein the tumor antigen is PSMA.
4. The method of claim 1 , wherein the antigen binding domain is a Fab or a scFv.
5. The method of claim 1 , wherein the tumor antigen is MUC1 (CA 15-3).
6. The method of claim 1 , wherein the transmembrane domain is a CD8 transmembrane domain.
7. The method of claim 1 , wherein the transmembrane domain is encoded by a nucleic acid sequence comprising nucleotides 924-995 of SEQ ID NO:1.
8. The method of claim 1 , wherein the CAR further comprises a hinge domain.
9. The method of claim 8 , wherein the hinge domain is a CD8 hinge domain.
10. The method of claim 1 , wherein the cancer is a solid tumor.
11. The method of claim 10 , wherein the solid tumor is of the breast, ovary, pancreas, or lung.
12. The method of claim 1 , wherein the cancer is a hematological cancer.
13. The method of claim 12 , wherein the hematological cancer is multiple myeloma.
14. The method of claim 1 , further comprising administering to the human a T cell ablative therapy in conjunction with the T cell genetically engineered to express the chimeric antigen receptor (CAR).
15. The method of claim 14 , wherein the T cell ablative therapy comprises administration of fludarabine and/or cyclophosphamide.
16. The method of claim 1 , wherein the administering is performed via intravenous delivery.
17. The method of claim 1 , wherein the administering is performed via intratumoral delivery.
18. A method of providing an anti-tumor immunity in a mammal in need thereof, the method comprising:
administering to the mammal an effective amount of a T cell genetically modified to express a chimeric antigen receptor (CAR),
wherein the CAR comprises:
an antigen binding domain that targets a tumor antigen selected from the group consisting of CD19, CD20, CD22, ROR1, mesothelin, CD33, IL3Ra, c-Met, PSMA, Glycolipid F77, EGFRvIII, GD-2, NY-ESO-1 TCR, MAGE A3 TCR, and MUC1 (CA15-3), and any combination thereof,
a transmembrane domain,
a costimulatory signaling region comprising a CD2 signaling domain and a CD28 signaling domain, or a CD2 signaling domain and a 4-1BB signaling domain, wherein the CD2 signaling domain is encoded by a nucleic acid sequence comprising nucleotides 996-1346 of SEQ ID NO: 1, and
a CD3 zeta signaling domain.
19. The method of claim 18 , wherein the cell is a T cell.
20. The method of claim 18 , wherein the mammal is a human.