Chimeric antigen receptors (CARs) have been used to redirect the specificity of autologous T cells against leukemia and lymphoma with promising clinical results. Extending this approach to allogeneic T cells is problematic as they carry a significant risk of graft-versus-host disease (GVHD). Natural killer (NK) cells are highly cytotoxic effectors, killing their targets in a non-antigen-specific manner without causing GVHD. Cord blood (CB) offers an attractive, allogeneic, off-the-self source of NK cells for immunotherapy. We transduced CB-derived NK cells with a retroviral vector incorporating the genes for CAR-CD19, IL-15 and inducible caspase-9-based suicide gene (iC9), and demonstrated efficient killing of CD19-expressing cell lines and primary leukemia cells in vitro, with marked prolongation of survival in a xenograft Raji lymphoma murine model. Interleukin-15 (IL-15) production by the transduced CB-NK cells critically improved their function. Moreover, iC9/CAR.19/IL-15 CB-NK cells were readily eliminated upon pharmacologic activation of the iC9 suicide gene. In conclusion, we have developed a novel approach to immunotherapy using engineered CB-derived NK cells, which are easy to produce, exhibit striking efficacy and incorporate safety measures to limit toxicity. This approach should greatly improve the logistics of delivering this therapy to large numbers of patients, a major limitation to current CAR-T-cell therapies.
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This work was funded in part by LLS 6470-15, ACS RSG-15-218-01-LIB and the generous philanthropic contributions to The University of Texas MD Anderson Moon Shots Program. The flow studies were performed in the Flow Cytometry & Cellular Imaging Facility, which is supported in part by the National Institutes of Health through MD Anderson Cancer Center Support Grant CA016672.
EL designed and performed experiments, interpreted the data and wrote the manuscript, YT, MaM, HS, XL, AR, MG, LL, MHB, XW, RC, RB and PB performed experiments and commented on the manuscript. GP, BS, MuM, JO, MK, DM, WW, RC and EJS provided advice on experiments and commented on the manuscript. KR designed and directed the study and wrote the manuscript.
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Leukemia website
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Journal of Clinical Investigation (2019)
Trends in Immunology (2019)
Seminars in Hematology (2019)
Advanced Drug Delivery Reviews (2019)
Archives of Pharmacal Research (2019)