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

Cancer Gene Therapy volume 29, pages 475–483 (2022)Cite this article

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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.

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Fig. 1: Overexpression of CXCR4R334X via mRNA electroporation can improve the migration and homing capacities of NK cells.
Fig. 2: Expression of anti-BCMA mRNA CAR on NK cells and BCMA expression on different tumor cells and primary cells.
Fig. 3: In vitro activity of anti-BCMA CAR-NK cells against MM cell lines KMS-11, KMS-18, and U266.
Fig. 4: In vitro functions of BCMA CAR-modified, CXCR4-overexpressing NK cells.
Fig. 5: In vivo control of MM growth by BMCA CAR-modified, CXCR4R334X-overexpressing NK cells.

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Funding

This work was supported by the Singapore Ministry of Health’s National Medical Research Council (NMRC/CIRG/1406/2014; NMRC/OFLCG/003/2018; MOH-000465-01) and Agency for Science, Technology and Research, Singapore (IAF-PP:H19/01/a0/022).

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Authors and Affiliations

  1. Department of Biological Sciences, National University of Singapore, Singapore, Singapore

    Yu Yang Ng, Zhicheng Du, Xi Zhang & Shu Wang

  2. Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, Singapore, Singapore

    Wee Joo Chng

  3. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

    Wee Joo Chng

  4. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    Wee Joo Chng

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Correspondence to Shu Wang.

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Ng, Y.Y., Du, Z., Zhang, X. et al. CXCR4 and anti-BCMA CAR co-modified natural killer cells suppress multiple myeloma progression in a xenograft mouse model. Cancer Gene Ther 29, 475–483 (2022). https://doi.org/10.1038/s41417-021-00365-x

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