CXCR4 and anti-BCMA CAR co-modified natural killer cells suppress multiple myeloma progression in a xenograft mouse model

Abstract

The highly restricted expression of B-cell maturation antigen (BCMA) on plasma cells makes it an ideal target for chimeric antigen receptor (CAR) immune cell therapy against multiple myeloma (MM), a bone marrow cancer. To improve the infiltration of ex vivo expanded human natural killer (NK) cells into the bone marrow, we electroporated these cells with mRNA encoding the chemokine receptor CXCR4. The CXCR4-modified NK cells displayed increased in vitro migration toward the bone marrow niche-expressing chemokine CXCL12/SDF-1α and augmented infiltration into the bone marrow compartments in mice. We further modified the CXCR4-NK cells by electroporation of mRNA encoding a CAR targeting BCMA. After the intravenous injection of the double-modified NK cells into a xenograft mouse model of MM, we observed significantly reduced tumor burden in the femur region of the living mice and the extended survival of the tumor-bearing mice. Collectively, this study provides the experimental evidence that the co-expression of CXCR4 and anti-BCMA CAR on NK cells is a possible effective way to control MM progression.

Trial registration: ClinicalTrials.gov NCT03940833 NCT03415100.