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 CAR T cell in the patient.

What is claimed is: 
     
         1 . A method of treating a patient having a disease, disorder or condition associated with an elevated expression of a tumor antigen, the method comprising administering a first-line therapy and a second-line therapy to a patient in need thereof, wherein the first line therapy comprises administering to the patient an effective amount of a cell genetically modified to express a CAR, wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain. 
     
     
         2 . The method of  claim 1 , wherein following the administration of the first-line therapy, cytokine levels in the patient are monitored to determine the appropriate type of second-line therapy to be administered to the patient and the appropriate second-line therapy is administered to the patient in need thereof. 
     
     
         3 . The method of  claim 2 , wherein an increase in the level of a cytokine identifies a type of cytokine inhibitory therapy to be administered to the patient in need thereof. 
     
     
         4 . The method of  claim 3 , wherein the cytokine is selected from the group consisting of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, IL-1Ra, IL-2R, IFN-α, IFN-γ, MIP-1α, MIP-1β, MCP-1, TNFα, GM-CSF, G-CSF, CXCL9, CXCL10, CXCR factors, VEGF, RANTES, EOTAXIN, EGF, HGF, FGF-β, CD40, CD40L, ferritin, and any combination thereof. 
     
     
         5 . The method of  claim 3 , wherein the cytokine inhibitory therapy is selected from the group consisting of a small interfering RNA (siRNA), a microRNA, an antisense nucleic acid, a ribozyme, an expression vector encoding a transdominant negative mutant, an antibody, a peptide, a small molecule, a cytokine inhibitory drug, and any combination thereof. 
     
     
         6 . The method of  claim 2 , wherein the cytokine levels are monitored by detecting the protein level of the cytokine in a biological sample from the patient. 
     
     
         7 . The method of  claim 2 , wherein the cytokine levels are monitored by detecting the nucleic acid level of the cytokine in a biological sample from the patient. 
     
     
         8 . A method of reducing or avoiding an adverse effect associated with the administration of a cell genetically modified to express a CAR, wherein the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain, the method comprising monitoring the levels of a cytokine in a patient to determine the appropriate type of cytokine therapy to be administered to the patient and administering the appropriate cytokine therapy to the patient. 
     
     
         9 . The method of  claim 8 , wherein an increase in the level of a cytokine identifies a type of cytokine inhibitory therapy to be administered to the patient. 
     
     
         10 . The method of  claim 9 , wherein the cytokine is selected from the group consisting of IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, IL-1Ra, IL-2R, IFN-α, IFN-γ, MIP-1α, MIP-1β, MCP-1, TNFα, GM-CSF, G-CSF, CXCL9, CXCL10, CXCR factors, VEGF, RANTES, EOTAXIN, EGF, HGF, FGF-β, CD40, CD40L, ferritin, and any combination thereof. 
     
     
         11 . The method of  claim 9 , wherein the cytokine inhibitory therapy is selected from the group consisting of a small interfering RNA (siRNA), a microRNA, an antisense nucleic acid, a ribozyme, an expression vector encoding a transdominant negative mutant, an intracellular antibody, a peptide, a small molecule, a cytokine inhibitory drug, and any combination thereof. 
     
     
         12 . The method of  claim 8 , wherein the cytokine levels are monitored by detecting the protein level of the cytokine in a biological sample from the patient. 
     
     
         13 . The method of  claim 8 , wherein the cytokine levels are monitored by detecting the nucleic acid level of the cytokine in a biological sample from the patient.