Modified Natural Killer Cells and Natural Killer Cell Lines Having Increased Cytotoxicity

Abstract

NK cells and NK cell lines are modified to increase cytotoxicity, wherein the cells and compositions thereof have a use in the treatment of cancer. Production of modified NK cells and NK cell lines is via genetic modification to remove checkpoint inhibitory receptor expression and/or add mutant (variant) TRAIL ligand expression.

1 - 20 . (canceled) 
     
     
         21 . A human natural killer (NK) cell or NK cell line modified to have reduced function, with respect to a wildtype NK cell or NK cell line, of a checkpoint inhibitory receptor selected from the group consisting of CD96 (TACTILE), CD152 (CTLA4), CD223 (LAG-3), CD279 (PD-1), CD328 (SIGLEC7), SIGLEC9, TIGIT, and TIM-3. 
     
     
         22 . The NK cell or NK cell line of  claim 21 , wherein the checkpoint inhibitory receptor is CD152 (CTLA4). 
     
     
         23 . The NK cell or NK cell line of  claim 21 , wherein the checkpoint inhibitory receptor is CD223 (LAG-3). 
     
     
         24 . The NK cell or NK cell line of  claim 21 , wherein the checkpoint inhibitory receptor is CD279 (PD-1). 
     
     
         25 . The NK cell or NK cell line of  claim 21 , wherein the checkpoint inhibitory receptor is SIGLEC9. 
     
     
         26 . The NK cell or NK cell line of  claim 21 , wherein the checkpoint inhibitory receptor is TIGIT. 
     
     
         27 . The NK cell or NK cell line of  claim 21 , wherein the checkpoint inhibitory receptor is TIM-3. 
     
     
         28 . The NK cell or NK cell line of  claim 21 , wherein the modification that reduces function of a checkpoint inhibitory receptor is a genetic modification to knock down or knock out a gene for the checkpoint inhibitory receptor. 
     
     
         29 . The NK cell or NK cell line of  claim 21  further modified to express a chimeric antigen receptor (CAR). 
     
     
         30 . The NK cell or NK cell line of  claim 29 , wherein the CAR binds CD38. 
     
     
         31 . A method of treating a cancer in an individual in need thereof, comprising administering to the individual a human NK cell or NK cell line which has been genetically modified, with respect to a wildtype NK cell or NK cell line, by knocking down or knocking out a gene for one or more checkpoint inhibitory receptors selected from the group consisting of CD152 (CTLA4), CD223 (LAG-3), CD279 (PD-1), SIGLEC9, TIGIT, and TIM-3. 
     
     
         32 . The method of  claim 31 , wherein the checkpoint inhibitory receptor is CD152 (CTLA4). 
     
     
         33 . The method of  claim 31 , wherein the checkpoint inhibitory receptor is CD223 (LAG-3). 
     
     
         34 . The method of  claim 31 , wherein the checkpoint inhibitory receptor is CD279 (PD-1). 
     
     
         35 . The method of  claim 31 , wherein the checkpoint inhibitory receptor is SIGLEC9. 
     
     
         36 . The method of  claim 31 , wherein the checkpoint inhibitory receptor is TIGIT. 
     
     
         37 . The method of  claim 31 , wherein the checkpoint inhibitory receptor is TIM-3. 
     
     
         38 . The method of  claim 31 , wherein the cancer is a blood cancer selected from the group consisting of acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), Hodgkin's lymphoma, non-Hodgkin's lymphoma, including T-cell lymphomas and B-cell lymphomas, multiple myeloma (MM), asymptomatic myeloma, smoldering multiple myeloma (SMM), active myeloma, and light chain myeloma. 
     
     
         39 . The method of  claim 31 , wherein the cancer is a solid cancer. 
     
     
         40 . The method of  claim 31 , wherein the NK cell or NK cell line is further modified to express a CAR. 
     
     
         41 . The method of  claim 40 , wherein the CAR binds CD38.