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 . (canceled)
2 . A method of treating a human patient with cancer, the method comprising administering to the human a T cell comprising a nucleic acid sequence that encodes a chimeric antigen receptor (CAR), wherein the CAR comprises a CD19 antigen binding domain, a transmembrane domain, a co-stimulatory signaling region and a CD3 zeta signaling domain, wherein prior to administration of the T cell to the human, the human is administered one or more lymphodepleting agents.
3 . The method of claim 2 , wherein the CD19 antigen binding domain is a Fab or scFv.
4 . The method of claim 3 , wherein the CD19 antigen binding domain is a scFv.
5 . The method of claim 2 , wherein the transmembrane domain comprises CD8 transmembrane domain.
5 . The method of claim 2 , wherein the co-stimulatory signaling region is 4-1BB.
6 . The method of claim 2 , wherein the CAR further comprises a hinge region.
7 . The method of claim 2 , wherein the hinge region comprises a CD8α hinge region.
8 . The method of claim 2 , wherein the one or more lymphodepleting agent is selected from the group consisting of fludarabine, cyclophosphamide, bendamustine, pentostatin, cyclosporine, external beam radiation therapy, OKT3 antibodies and CAMPATH antibodies.
9 . The method of claim 8 , wherein the one or more lymphodepleting agent is selected from the group consisting of fludarabine, cyclophosphamide and bendamustine.
10 . The method of claim 2 , wherein the cancer is a hematologic cancer.
11 . The method of claim 10 , wherein the hematologic cancer is selected from the group consisting of acute lymphocytic leukemia, acute myelocytic leukemia, acute myelogenous leukemia, myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic eukemia, erythroleukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, polycythemia vera, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL), multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, myelodysplastic syndrome, hairy cell leukemia and myelodysplasia.
12 . The method of claim 11 , wherein the hematologic cancer is acute lymphocytic leukemia or DLBCL.
13 . The method of claim 12 , wherein the lymphodepleting agent is selected from the group consisting of fludarabine, cyclophosamide and bendamustine.
14 . The method of claim 12 , wherein the human is administered the CAR after the administration of the lymphodepleting agent is complete.
15 . A method of treating acute lymphocytic leukemia in a human patient, the method comprising administering to the human a T cell comprising a nucleic acid sequence that encodes a chimeric antigen receptor (CAR), wherein the CAR comprises a CD19 antigen binding domain, a transmembrane domain, a co-stimulatory signaling region and a CD3 zeta signaling domain, wherein prior to administration of the T cell to the human, the human is administered one or more of fludarabine and cyclosphophamide.
16 . A method of treating diffuse large B-cell lymphoma (DLBCL) in a human patient, the method comprising administering to the human a T cell comprising a nucleic acid sequence that encodes a chimeric antigen receptor (CAR), wherein the CAR comprises a CD19 antigen binding domain, a transmembrane domain, a co-stimulatory signaling region and a CD3 zeta signaling domain, wherein prior to administration of the T cell to the human, the human is administered one or more of fludarabine, cyclosphophamide and bendamustine.