Inhibition of cytokine-induced sh2 protein in nk cells

Abstract

The present invention relates to therapeutic and prophylactic methods based on inhibition of CIS in NK cells. In particular, the present invention relates to treating or preventing a NK-responsive condition by administering to a subject a CIS inhibitor, or administering CIS-inhibited NK cells. The invention further relates to methods for identifying a CIS inhibitor, and for determining a likelihood of cancer response to treatment with CIS inhibition

1 - 64 . (canceled) 
     
     
         65 . A method for adoptive cell therapy or prophylaxis, comprising administering CIS-inhibited NK cells to a subject suffering from or determined to be at risk of suffering from a cancer or an infection, wherein the CIS-inhibited NK cells are NK cells genetically modified to have reduced expression of CIS, or are modified to express a dominant negative CIS sequence variant or dominant negative fragment thereof, wherein the method further comprises administering a transforming growth factor beta receptor (TGFBR) antagonist to the subject. 
     
     
         66 . The method of  claim 65 , wherein the CIS-inhibited NK cells and the TGFBR antagonist are administered in combination. 
     
     
         67 . The method of  claim 65 , wherein the TGFBR antagonist is specific for TGFBR2. 
     
     
         68 . The method of  claim 65 , wherein the CIS-inhibited NK cells are genetically modified to have reduced expression of a TGFBR. 
     
     
         69 . The method of  claim 68 , wherein the CIS-inhibited NK cells are genetically modified to have reduced expression of TGFBR2. 
     
     
         70 . The method of  claim 65 , wherein the method further comprises administering IL-15. 
     
     
         71 . The method of  claim 65 , wherein the CIS-inhibited NK cells are genetically modified to have reduced expression of CIS. 
     
     
         72 . The method of  claim 71 , wherein the CIS-inhibited NK cells are Cish −/− . 
     
     
         73 . The method of  claim 65 , wherein the CIS-inhibited NK cells are Cish −/−  and TGFBR2-deficient. 
     
     
         74 . The method of  claim 65 , wherein the subject is suffering from a cancer, or is determined to be at risk of suffering from a cancer. 
     
     
         75 . The method of  claim 74 , wherein the cancer is selected from the group consisting of: metastatic melanoma, metastatic prostate cancer, metastatic breast cancer, triple negative breast cancer, bladder cancer, brain cancer, esophageal cancer, liver cancer, head and neck cancer, squamous cell lung cancer, non-small lung cell cancer, Merkel cell carcinoma, sarcoma, hepatocellular cancer, multiple myeloma, pancreatic cancer, colorectal carcinoma, cervical cancer, gastric carcinoma, kidney cancer, metastatic renal cell carcinoma, leukemia, ovarian cancer, and malignant glioma. 
     
     
         76 . The method of  claim 65 , wherein the CIS-inhibited NK cells comprise a deletion or a substitution in the Cish gene. 
     
     
         77 . The method of  claim 65 , wherein administering a TGFBR antagonist comprises administering NK cells comprising a deletion or a substitution in a TGFBR gene. 
     
     
         78 . The method of  claim 65 , comprising administering NK cells that comprise a deletion or a substitution in the Cish gene and also a deletion or a substitution in a TGFBR gene.