NK cells with altered CXCL12/CXCR4 signaling
NK cell based cancer immunotherapy, and particularly genetically modified NK92 cell-based immunotherapy is enhanced by expression CXCL12 and/or by suppression or deletion of CXCR4 in the natural killer cells to so reduce aggregation, rejection, and/or fratricide of the natural killer cells. Provided herein are genetically engineered NK (natural killer) cell comprising a recombinant nucleic acid encoding at least a portion of chemokine C—X—C motif ligand 12 (CXCL12), and a transcript for downregulation of chemokine C—X—C motif receptor 4 (CXCR4).
1. A genetically engineered NK (natural killer) cell comprising a recombinant nucleic acid encoding at least a portion of chemokine C—X—C motif ligand 12 (CXCL12), and a transcript for downregulation of chemokine C—X—C motif receptor 4 (CXCR4), wherein the transcript for downregulation of CXCR4 is an shRNA or an siRNA.
2. The NK cell of claim 1 wherein the natural killer cell is genetically engineered to express a high-affinity Fcγ receptor or a chimeric T-cell receptor.
3. The NK cell of claim 1 wherein the cell is genetically engineered to have a reduced or abolished expression, relative to an unmodified NK cell, of at least one killer cell immunoglobulin-like receptor (KIR).
4. The NK cell of claim 3 wherein the at least a portion of CXCL12 is a full length variant of CXCL12.
5. The NK cell of claim 3 wherein the at least a portion of CXCL12 is a truncated agonist variant of CXCL12 that binds to CXCR4.
6. The NK cell of claim 1 wherein the cell has the deletion or knockout mutation for CXCR4.
7. A pharmaceutical composition comprising the genetically engineered natural killer cell according to claim 1 .
8. The pharmaceutical composition of claim 7 further comprising an immune checkpoint inhibitor.
9. A genetically engineered NK cell comprising a recombinant nucleic acid encoding at least a portion of CXCL12, and wherein the NK cell is further modified to have a deletion or knockout mutation for CXCR4.
10. The NK cell of claim 9 wherein the natural killer cell is genetically engineered to express a high-affinity Fcγ receptor or a chimeric T-cell receptor.
11. The NK cell of claim 9 wherein the cell is genetically engineered to have a reduced or abolished expression, relative to an unmodified NK cell, of at least one KIR.
12. The NK cell of claim 11 wherein the at least a portion of CXCL12 is a full length variant of CXCL12.
13. The NK cell of claim 11 wherein the at least a portion of CXCL12 is a truncated agonist variant of CXCL12 that binds to CXCR4.
14. A pharmaceutical composition comprising the genetically engineered natural killer cell according to claim 5 .
15. The pharmaceutical composition of claim 14 further comprising an immune checkpoint inhibitor.