Materials and methods for treating cancer

Abstract

This document provides methods and materials involved in treating cancer. For example, chimeric antigen receptor T cells having reduced levels of GM-CSF are provided. Also provided as methods for making and using chimeric antigen receptor T cells having reduced levels of GM-CSF.

What is claimed is: 
     
         1 . A method for treating or preventing CAR-T cell related toxicity in a subject in need thereof, the method comprising administering to the subject CAR-T cells having a GM-CSF gene inactivation, GM-CSF gene knock-down or gene knockout (GM-CSF k/o  CAR-T cells). 
     
     
         2 . The method of  claim 1 , wherein the CAR-T cell related toxicity comprises neurotoxicity, cytokine release syndrome (CRS) or a combination thereof. 
     
     
         3 . The method of  claim 1 , wherein the subject has a cancer and/or a tumor. 
     
     
         4 . The method of  claim 3 , wherein the cancer is lymphoma or a leukemia. 
     
     
         5 . The method of  claim 4 , wherein the lymphoma is a diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma, or follicular lymphoma. 
     
     
         6 . The method of  claim 4 , wherein the leukemia is acute lymphoblastic leukemia (ALL). 
     
     
         7 . The method of  claim 3 , wherein the cancer is multiple myeloma. 
     
     
         8 . The method of  claim 1 , wherein the GM-CSF k/o  CAR-T cells target tumor antigen CD19 on lymphoma or leukemia cancer cells. 
     
     
         9 . The method of  claim 1 , wherein the GM-CSF k/o  CAR-T cells target tumor antigen BCMA on multiple myeloma cells. 
     
     
         10 . The method of  claim 3 , wherein levels of the CAR-T cells having a GM-CSF gene inactivation, GM-CSF gene knock-down or gene knockout (GM-CSF k/o  CAR-T cells) expand and persist in blood of the subject from a peak level of GM-CSF k/o  CAR-T cell expansion during the first 30 days after administration of the GM-CSF k/o  CAR-T cells and expansion of the GM-CSF k/o  CAR-T cells up to at least 90 days to 180 days after the administration of the GM-CSF k/o  CAR-T cells. 
     
     
         11 . The method of  claim 10 , wherein GM-CSF k/o  CAR-T cell expansion and persistence in the blood of the subject continues for up to 24 months after administration of the GM-CSF k/o  CAR-T cells. 
     
     
         12 . The method of  claim 10 , wherein GM-CSF k/o  CAR-T cell expansion and persistence in the blood of the subject achieves an anti-cancer or anti-tumor efficacy from 90 days to 24 months after administration of the GM-CSF k/o  CAR-T cells. 
     
     
         13 . The method of  claim 10 , wherein GM-CSF k/o  CAR-T cells peak expansion is enhanced relative to wild type (wt) CAR-T cells and persistence as measured by CAR area under the curve (AUC) is improved relative to wt CAR-T cells. 
     
     
         14 . The method of  claim 13 , wherein improved GM-CSF k/o  CAR-T cell expansion and persistence results in improved objective response rates (ORR), improved progression free survival (PFS), or improved overall survival (OS) compared to wt CAR-T cells. 
     
     
         15 . The method of  claim 12 , wherein the anti-cancer or anti-tumor efficacy in the subject is a complete or partial remission of the cancer and/or the tumor. 
     
     
         16 . The method of  claim 12 , wherein the anti-cancer or anti-tumor efficacy in the subject is a reduction or an absence of signs and symptoms of the cancer and/or the tumor. 
     
     
         17 . A method for increasing CAR-T cell proliferation in a subject treated with GM-CSF-inactivated or GM-CSF k/o  CAR-T cells, the method comprising administering to the subject CAR-T cells having a GM-CSF gene inactivation, GM-CSF gene knock-down or gene knockout (GM-CSF k/o  CAR-T cells), wherein administration of the GM-CSF k/o  CAR-T cells increases CAR-T proliferation in the subject. 
     
     
         18 . The method of  claim 17 , wherein administration of the GM-CSF k/o  CAR-T cells and expansion of the GM-CSF k/o  CAR-T cells reduces production of GM-CSF by 75%-99% or eliminates production of GM-CSF by the GM-CSF k/o  CAR-T cells. 
     
     
         19 . The method of  claim 18 , wherein reduction or elimination of the production of GM-CSF by the GM-CSF k/o  CAR-T cells increases production and expansion of the GM-CSF by the GM-CSF k/o  CAR-T cells. 
     
     
         20 . The method of  claim 19 , wherein increased production and expansion of the GM-CSF by the GM-CSF k/o  CAR-T cells reduces of eliminates CAR-T cell related toxicity in the subject, wherein the CAR-T cell related toxicity comprises neurotoxicity, cytokine release syndrome (CRS) or a combination thereof. 
     
     
         21 . The method of  claim 17 , wherein the subject has a cancer and/or a tumor. 
     
     
         22 . The method of  claim 21 , wherein the cancer is lymphoma or a leukemia. 
     
     
         23 . The method of  claim 22 , wherein the lymphoma is a diffuse large B cell lymphoma (DLBCL). 
     
     
         24 . The method of  claim 22 , wherein the leukemia is acute lymphoblastic leukemia (ALL). 
     
     
         25 . The method of  claim 21 , wherein the cancer is multiple myeloma. 
     
     
         26 . The method of  claim 17 , wherein the GM-CSF k/o  CAR-T cells target tumor antigen CD19 on lymphoma or leukemia cancer cells. 
     
     
         27 . The method of  claim 17 , wherein the GM-CSF k/o  CAR-T cells target tumor antigen BCMA on multiple myeloma cells. 
     
     
         28 . The method of  claim 18 , wherein levels of the CAR-T cells having a GM-CSF gene inactivation, GM-CSF gene knock-down or gene knockout (GM-CSF k/o  CAR-T cells) expand and persist in blood of the subject from a peak level of GM-CSF k/o  CAR-T cell expansion during the first 30 days after administration of the GM-CSF k/o  CAR-T cells and expansion of the GM-CSF k/o  CAR-T cells up to at least 90 days to 180 days after the administration of the GM-CSF k/o  CAR-T cells. 
     
     
         29 . The method of  claim 28 , wherein GM-CSF k/o  CAR-T cell expansion and persistence in the blood of the subject continues for up to 24 months after administration of the GM-CSF k/o  CAR-T cells. 
     
     
         30 . The method of  claim 28 , wherein GM-CSF k/o  CAR-T cell expansion and persistence in the blood of the subject achieves an anti-cancer or anti-tumor efficacy from 90 days to 24 months after administration of the GM-CSF k/o  CAR-T cells. 
     
     
         31 . The method of  claim 28 , wherein GM-CSF k/o  CAR-T cells peak expansion is enhanced relative to wt CAR-T cells and persistence as measured by CAR area under the curve (AUC) is improved relative to wt CAR-T cells. 
     
     
         32 . The method of  claim 31 , wherein improved GM-CSF k/o  CAR-T cell expansion and persistence results in improved objective response rates (ORR), improved progression free survival (PFS), or improved overall survival (OS) compared to wt CAR-T cells. 
     
     
         33 . The method of  claim 30 , wherein the anti-cancer or anti-tumor efficacy in the subject is a complete or partial remission of the cancer and/or the tumor. 
     
     
         34 . The method of  claim 30 , wherein the anti-cancer or anti-tumor efficacy in the subject is a reduction or an absence of signs and symptoms of the cancer and/or the tumor.