Compositions and methods for treatment of cancer
The present invention provides compositions and methods for treating cancer in a human. The invention includes relates to administering a genetically modified T cell to express a CAR wherein the CAR comprises an antigen binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain.
1. A human T cell comprising a nucleic acid sequence encoding a chimeric antigen receptor (CAR), wherein the CAR comprises a CD19 antigen binding domain comprising, from the amino to the carboxy terminus, a light chain variable region and a heavy chain variable region of SEQ ID NO:20, wherein the CAR further comprises a transmembrane domain, a 4-1BB costimulatory signaling region, and a CD3 zeta signaling domain, wherein the T cells is from a human having cancer.
2. The human T cell of claim 1 , wherein said antigen binding fragment is a scFv.
3. The human T cell of claim 2 , wherein the scFv comprises the amino acid sequence of SEQ ID NO:20.
4. The human T cell of claim 1 , wherein the transmembrane domain is CD8α transmembrane domain.
5. The human T cell of claim 4 , wherein the CD8α transmembrane domain comprises the amino acid sequence of SEQ ID NO: 22.
6. The human T cell of claim 1 , wherein the CAR further comprises a hinge domain.
7. The human T cell of claim 6 , wherein the hinge domain is a CD8α hinge domain.
8. The human T cell of claim 7 , wherein the CD8α hinge domain comprises the amino acid sequence of SEQ ID NO:21.
9. The human T cell of claim 1 , wherein the 4-1BB costimulatory signaling region comprises the amino acid sequence of SEQ ID NO:23.
10. The human T cell of claim 1 , wherein the CD3 zeta signaling domain comprises the amino acid sequence of SEQ ID NO: 24.
11. The human T cell of claim 1 , wherein the CD19 antigen binding domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 14.
12. The human T cell of claim 5 , wherein the CD8α transmembrane domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 16.
13. The human T cell of claim 8 , wherein the CD8α hinge domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 15.
14. The human T cell of claim 9 , wherein the 4-1BB costimulatory signaling region is encoded by a nucleic acid sequence comprising SEQ ID NO: 17.
15. The human T cell of claim 10 , wherein the CD3 zeta signaling domain is encoded by a nucleic acid sequence comprising SEQ ID NO: 18.
16. The human T cell of claim 1 , wherein the CAR comprises the amino acid sequence of SEQ ID NO:12.
17. The human T cell of claim 16 , wherein the CAR is encoded by a nucleic acid sequence comprising SEQ ID NO:8.
18. The human T cell of claim 1 , wherein the CAR further comprises a CD28 costimulatory signaling region.
19. The human T cell of claim 1 , wherein the cancer is a hematological cancer.
20. The human T cell of claim 1 , wherein the T cell comprises a vector that comprises the nucleic acid sequence.
21. The human T cell of claim 20 , wherein the vector is a lentiviral vector.
22. The human T cell of claim 21 , wherein the vector further comprises a promoter.
23. The human T cell of claim 22 , wherein the promoter is an EF-1α promoter.
24. The human T cell of claim 1 , wherein the cell is isolated from a blood sample obtained from a human before the human is treated with a modality selected from the group consisting of an antiviral agent, chemotherapy, radiation, an immunosuppressive agent and an antibody.
25. The human cell of claim 24 , wherein the antibody is selected from the group consisting of anti-CD3 antibody, natalizumab and efalizumab.
26. The human cell of claim 24 , wherein the immunosuppressive agent is selected from the group consisting of cyclosporin, azathioprine, methotrexate, mycophenolate, FK506, CAMPATH, cytoxan, fludarabine, cyclosporin, FK506, rapamycin, mycophenolic acid, a steroid, and FR901228.