Toxicity Management for Anti-Tumor Activity of CARs

Abstract

The present invention provides compositions and methods for treating cancer in a patient. In one embodiment, the method comprises a first-line therapy comprising administering to a patient in need thereof a genetically modified T cell expressing a CAR wherein the CAR comprises an antigen binding domain, a transmembrane domain, a costimulatory signaling region, and a CD3 zeta signaling domain and monitoring the levels of cytokines in the patient post T cell infusion to determine the type of second-line of therapy appropriate for treating the patient as a consequence of the presence of the CART cell in the patient.

1 - 18 . (canceled) 
     
     
         19 . A method of treating cytokine release syndrome comprising administering to a human in need thereof an IL-6 inhibitor in conjunction with a steroid, wherein said human has received a chimeric antigen receptor (CAR) T cell therapy, and has cytokine release syndrome; wherein said CAR comprises an extracellular domain having an antigen recognition domain, a transmembrane domain, and an intracellular signaling domain. 
     
     
         20 . The method of  claim 19 , wherein said IL-6 inhibitor is tocilizumab. 
     
     
         21 . The method of  claim 20 , wherein said tocilizumab is administered at a dose of 8 mg/kg body weight of said human. 
     
     
         22 . The method of  claim 20 , wherein said steroid is methylprednisolone. 
     
     
         23 . The method of  claim 22 , wherein said methylprednisolone is administered at a dose of 2 mg/kg body weight of said human. 
     
     
         24 . The method of  claim 20 , wherein said tocilizumab is administered prior to the administration of said steroid. 
     
     
         25 . The method of  claim 20 , wherein said tocilizumab is administered after the administration of said steroid. 
     
     
         26 . The method of  claim 20 , wherein said tocilizumab is administered concurrently with said steroid. 
     
     
         27 . The method of  claim 20 , wherein said antigen is a B cell antigen. 
     
     
         28 . The method of  claim 27 , wherein said antigen is CD19. 
     
     
         29 . The method of  claim 28 , wherein said intracellular signaling domain comprises a CD137 (4-1BB) signaling domain, and a CD3 zeta signaling domain. 
     
     
         30 . The method of  claim 28 , wherein said intracellular signaling domain comprises a CD28 signaling domain, and a CD3 zeta signaling domain. 
     
     
         31 . The method of  claim 20 , wherein said human has cancer. 
     
     
         32 . The method of  claim 31 , wherein said cancer is a hematological malignancy. 
     
     
         33 . The method of  claim 31 , wherein said cancer is selected from the group consisting of:
 (i) a hematological malignancy selected from the group consisting of acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myelogenous leukemia, myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, polycythemia vera, lymphoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease, myelodysplastic syndrome, hairy cell leukemia and myelodysplasia;   (ii) pre-B ALL (pediatric indication), adult ALL, mantle cell lymphoma, diffuse large B cell lymphoma;   (iii) a solid tumor;   (iv) a primary or metastatic cancer; and   (v) a cancer that is refractory or resistant to conventional chemotherapy.   
     
     
         34 . The method of  claim 20 , wherein said cytokine release syndrome leads to hemophagocytic lymphohistiocytosis and/or macrophage activation syndrome. 
     
     
         35 . The method of  claim 20 , wherein the tocilizumab is administered to the human more than once. 
     
     
         36 . The method of  claim 20 , wherein the steroid is administered to the human more than once. 
     
     
         37 . The method of  claim 20 , further comprising administering to said human in need thereof an IL-1 inhibitor. 
     
     
         38 . The method of  claim 37 , wherein said IL-1 inhibitor is anakinra.