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. A natural killer (NK) cell or NK cell line that has been modified to have reduced function, with respect to a wildtype NK cell or NK cell line, of one or more checkpoint inhibitory receptors, and wherein the NK cell or NK cell line is further modified to express a mutant TRAIL ligand with an increased affinity for TRAIL receptors and/or a reduced affinity for decoy TRAIL receptors.
2. The NK cell or NK cell line of claim 1 , wherein the NK cell or NK cell line is human.
3. The NK cell or NK cell line of claim 1 , wherein the checkpoint inhibitory receptors are selected from the group consisting of CD96 (TACTILE), CD152 (CTLA4), CD223 (LAG-3), CD279 (PD-1), CD328 (SIGLEC7), SIGLEC9, TIGIT, and TIM-3.
4. The NK cell or NK cell line of claim 3 , wherein the checkpoint inhibitory receptors are selected from the group consisting of CD96 (TACTILE) and CD328 (SIGLEC7).
5. A natural killer (NK) cell line that has been modified to have reduced function, with respect to a wildtype NK cell line, of one or more checkpoint inhibitory receptors, wherein the NK cell line is further modified to express a mutant TRAIL ligand with an increased affinity for TRAIL receptors and/or a reduced affinity for decoy TRAIL receptors and wherein the cell line is a derivative of the KHYG-1 cell line.
6. The NK cell or NK cell line of claim 1 , wherein the modification that reduces function of a checkpoint inhibitory receptor is a genetic modification.
7. A human natural killer (NK) cell or NK cell line that has been genetically modified, with respect to a wildtype NK cell or NK cell line, by knocking out a gene for a checkpoint inhibitory receptor selected from the group consisting of CD96 (TACTILE) and CD328 (SIGLEC7).
8. A method of treating a cancer in an individual in need thereof, comprising administering to the individual a 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 one or more checkpoint inhibitory receptors and further modified to express a mutant TRAIL ligand with an increased affinity for TRAIL receptors and/or a reduced affinity for decoy TRAIL receptors.
9. The method of claim 8 , wherein the NK cell or NK cell line is human.
10. The method of claim 8 , wherein the checkpoint inhibitory receptors are selected from the group consisting of CD96 (TACTILE), CD152 (CTLA4), CD223 (LAG-3), CD279 (PD-1), CD328 (SIGLEC7), SIGLEC9, TIGIT, and TIM-3.
11. The method of claim 10 , wherein the checkpoint inhibitory receptors are selected from the group consisting of CD96 (TACTILE) and CD328 (SIGLEC7).
12. The method of claim 8 , 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 (CIVIL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, T-cell lymphoma, B-cell lymphoma, asymptomatic myeloma, smoldering multiple myeloma (SMM), active myeloma, and light chain myeloma.
13. A method of treating a cancer in an individual in need thereof, comprising administering to the individual a natural killer (NK) cell line modified to have reduced function, with respect to a wildtype NK cell line, of one or more checkpoint inhibitory receptors, wherein the NK cell line is further modified to express a mutant TRAIL ligand with an increased affinity for TRAIL receptors and/or a reduced affinity for decoy TRAIL receptors, and wherein the cell line is a derivative of the KHYG-1 cell line.
14. The method of claim 8 , wherein the NK cell or NK cell line targets the bone marrow.
15. The method of claim 8 , wherein the modification that reduces function of a checkpoint inhibitory receptor is a genetic modification.
16. A method of treating a blood cancer in an individual, comprising administering to the individual the human NK cell or NK cell line of claim 7 .