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