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Leukemia. 2018 Feb;32(2):520-531. doi: 10.1038/leu.2017.226. Epub 2017 Jul 20.

Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity.

Author information

1
Department of Stem Cell Transplantation and Cellular Therapy, MD Anderson Cancer Center, Houston, TX, USA.
2
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC, USA.
3
The Center for Human Immunobiology, Baylor College of Medicine, Houston, TX, USA.
4
Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA.
5
Department of Veterinary Medicine & Surgery, MD Anderson Cancer Center, Houston, TX, USA.
6
Department of Leukemia, MD Anderson Cancer Center, Houston, TX, USA.

Abstract

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.

PMID:
28725044
PMCID:
PMC6063081
[Available on 2019-02-01]
DOI:
10.1038/leu.2017.226

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