Modified NK-92 cells for treating cancer
Provided herein are NK-92 cells expressing at least one CAR and at least one Fc receptor. Also provided are methods of treatment of a patient having or suspected of having a disease that is treatable with NK-92 cells, such as cancer, comprising administering to the patient NK-92-Fc-CAR.
1. A method of treating a B-cell malignancy in a patient in need thereof, the method comprising administering to the patient an effective amount of an NK-92 cell line comprising modified NK-92 cells, wherein the modified NK-92 cells are modified to each express at least one Fc receptor and at least one chimeric antigen receptor (CAR), such that the at least one Fc receptor and the at least one CAR are displayed on the cell surface of the modified NK-92 cells, wherein the CAR comprises the amino acid sequence as defined in SEQ ID NO:9.
2. The method of claim 1 , wherein the Fc receptor is FcγRIII-A (CD16) or a CD16 polypeptide having a valine at position 158 of the mature form of the CD16.
3. The method of claim 1 , wherein the Fc receptor comprises an amino acid sequence having at least 90% sequence identity to SEQ ID NO:2 and comprises valine at position 158.
4. The method of claim 1 , wherein the Fc receptor comprises the amino acid sequence of SEQ ID NO:2.
5. The method of claim 1 , wherein the CAR targets the CD19 tumor-associated antigen.
6. The method of claim 1 , wherein the modified NK-92 cells are further modified to express a cytokine.
7. The method of claim 6 , wherein the cytokine is interleukin-2 or a variant thereof and/or interleukin-15 or a variant thereof.
8. The method of claim 7 , wherein the cytokine is targeted to the endoplasmic reticulum.
9. The method of claim 1 , wherein the Fc receptor and the CAR are encoded on different vectors.
10. The method of claim 1 , wherein the modified NK-92 cells have undergone less than 10 population doublings.
11. The method of claim 1 , wherein the modified NK-92 cells are administered to the patient by a route selected from the group consisting of intravenous, intraperitoneal, and subcutaneous.
12. The method of claim 1 , wherein the B-cell malignancy is selected from the group consisting of a leukemia, chronic B-cell leukemia, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), ALL post hematopoietic stem cell transplantation (HSCT), a lymphoma, Waldenstrom's macroglobulinemia, heavy chain disease, non-Hodgkin's lymphoma (NHL), refractory follicular lymphoma; B-cell non-Hodgkin lymphoma (B-NHL), B-cell malignancies post-HSCT, and B-lineage lymphoid malignancies post umbilical cord blood transplantation (UCBT).
13. The method of claim 1 , wherein about 1×10 8 to about 1×10 11 modified NK-92 cells per m 2 of body surface area of the patient are administered to the patient.
14. The method of claim 1 , further comprising administering to the patient an effective amount of at least one monoclonal antibody.
15. The method of claim 14 , wherein the monoclonal antibody is a naked monoclonal antibody, a conjugated monoclonal antibody or a bispecific monoclonal antibody.
16. The method of claim 14 , wherein the monoclonal antibody is selected from the group consisting of alemtuzumab, rituxumab, trastuzumab, ibritumomab, brentuximab, gemtuzumab, adotranstuzumab, blinatunomab, avelumamab, daratumumab and elotuzumab.
17. The method of claim 14 , wherein the monoclonal antibody and the modified NK-92 cells are administered concurrently to the patient.
18. The method of claim 1 , further comprising administering stem cell transplantation to the patient.
19. A method of treating a B-cell malignancy in a patient in need thereof, the method comprising administering to the patient an effective amount of an NK-92 cell line comprising modified NK-92 cells,
wherein the modified NK-92 cells are modified to each express at least one Fc receptor and at least one chimeric antigen receptor (CAR), such that the at least one Fc receptor and the at least one CAR are displayed on the cell surface of the modified NK-92 cells, and
wherein the CAR comprises an antibody comprising the amino acid sequences of the six CDRs of SEQ ID NO:9.
20. The method of claim 19 , wherein the Fc receptor is FcγRIII-A (CD16) or a CD16 polypeptide having a valine at position 158 of the mature form of the CD16.