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 method of treating a DR5-expressing and/or DR5-inducible blood cancer in an individual in need thereof, comprising administering to the individual a natural killer (NK) cell or NK cell line modified to express a TRAIL variant, wherein the TRAIL variant has an increased affinity for a DR5 TRAIL receptor compared to wildtype TRAIL, and wherein the TRAIL variant comprises mutations D269H and E195R, wherein the blood cancer is a DR5-expressing and/or DR5-inducing blood cancer.
2. The method of claim 1 , wherein the TRAIL variant has a reduced affinity for a decoy TRAIL receptor.
3. The method of claim 1 , further comprising administering to the individual an effective amount of a proteasome inhibitor.
4. The method of claim 3 , wherein the proteasome inhibitor is bortezomib.
5. The method of claim 1 , wherein the NK cell or NK cell line further comprises a modification that reduces or abolishes expression of a checkpoint inhibitory receptor.
6. The method of claim 5 , wherein the checkpoint inhibitory receptor is CD96 (TACTILE), CD152 (CTLA4), CD223 (LAG-3), CD279 (PD-1), CD328 (SIGLEC7), SIGLEC9, TIGIT or TIM-3.
7. The method of claim 1 , wherein the NK cell or NK cell line targets the bone marrow.
8. The method of claim 7 , wherein the NK cell or NK cell line further comprise a modification to express fucosyltransferase or sialyltransferase.
9. The method of claim 1 , wherein the NK cell line is a KHYG-1 cell line or a derivative thereof.
10. The method of claim 1 , wherein the blood cancer is acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), Hodgkin's lymphoma, non-Hodgkin's lymphoma, T-cell lymphoma, B-cell lymphoma, asymptomatic myeloma, multiple myeloma, smoldering multiple myeloma (SMM), active myeloma, or light chain myeloma.
11. The method of claim 1 , wherein the blood cancer is chronic myeloid leukemia or multiple myeloma.
12. The method of claim 1 , wherein the blood cancer is chronic myeloid leukemia or multiple myeloma, and wherein the NK cell line is a KHYG-1 cell line.