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 add mutant (variant) TRAIL ligand expression.
1. A method of treating a TRAIL-expressing 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 mutant, wherein the TRAIL mutant has an increased affinity for a TRAIL receptor and/or a decreased affinity for a decoy TRAIL receptor, relative to wildtype TRAIL.
2. The method of claim 1 , wherein the blood cancer is selected from 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, active myeloma, and light chain myeloma.
3. The method of claim 1 , further comprising administering to the individual an effective amount of an agent that upregulates expression of DR5 and/or DR4.
4. The method of claim 3 , wherein the agent is a proteasome inhibitor.
5. The method of claim 4 , wherein the proteasome inhibitor is bortezomib.
6. 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.
7. The method of claim 6 , wherein the checkpoint inhibitory receptor is selected from CD96 (TACTILE), CD152 (CTLA4), CD223 (LAG-3), CD279 (PD-1), CD328 (SIGLEC7), SIGLEC9, TIGIT, and TIM-3.
8. A method of treating a DR4-expressing 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 mutant, wherein the TRAIL mutant has an increased affinity for a DR4 TRAIL receptor, relative to wildtype TRAIL, and wherein the TRAIL mutant comprises mutations G131R, R149I, S159R and S215D, wherein the blood cancer is a DR4-expressing blood cancer.
9. The method of claim 8 , wherein the blood cancer is selected from 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, active myeloma, and light chain myeloma.