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Myeloma

CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma

Abstract

Multiple myeloma (MM) is an incurable hematological malignancy. Chimeric antigen receptor (CAR)-expressing T cells have been demonstrated successfully in the clinic to treat B-lymphoid malignancies. However, the potential utility of antigen-specific CAR-engineered natural-killer (NK) cells to treat MM has not been explored. In this study, we determined whether CS1, a surface protein that is highly expressed on MM cells, can be targeted by CAR NK cells to treat MM. We successfully generated a viral construct of a CS1-specific CAR and expressed it in human NK cells. In vitro, CS1-CAR NK cells displayed enhanced MM cytolysis and interferon-γ (IFN-γ) production, and showed a specific CS1-dependent recognition of MM cells. Ex vivo, CS1-CAR NK cells also showed similarly enhanced activities when responding to primary MM tumor cells. More importantly, in an aggressive orthotopic MM xenograft mouse model, adoptive transfer of NK-92 cells expressing CS1-CAR efficiently suppressed the growth of human IM9 MM cells and also significantly prolonged mouse survival. Thus, CS1 represents a viable target for CAR-expressing immune cells, and autologous or allogeneic transplantation of CS1-specific CAR NK cells may be a promising strategy to treat MM.

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Acknowledgements

The project was supported in part by Multiple Myeloma Opportunities for Research and Education (MMORE), and grants from the National Institutes of Health (CA155521 and 1R41OD018403 to JY and CA095426 and CA068458 to MAC), a 2012 scientific research grant from the National Blood Foundation (JY), an institutional research grant (IRG-67-003-47) from the American Cancer Society (JY), and The Ohio State University Comprehensive Cancer Center Pelotonia grant (JY).

AUTHOR CONTRIBUTIONS

JC designed research, performed experiments, and wrote the paper; YD, SH, YP, HM and LY performed experiments; DMB, KG, XH, SMD, XZ and MAC designed the research; TH reviewed and edited the manuscript; JZ analyzed the data; CCH devised the concept, designed the research and reviewed the manuscript; JY devised the concept, designed the research, supervised the study, and wrote the paper.

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Correspondence to C C Hofmeister or J Yu.

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Chu, J., Deng, Y., Benson, D. et al. CS1-specific chimeric antigen receptor (CAR)-engineered natural killer cells enhance in vitro and in vivo antitumor activity against human multiple myeloma. Leukemia 28, 917–927 (2014). https://doi.org/10.1038/leu.2013.279

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  • DOI: https://doi.org/10.1038/leu.2013.279

Keywords

  • CS1
  • chimeric antigen receptor
  • NK cells
  • multiple myeloma

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