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Cell Stem Cell. 2018 Aug 2;23(2):181-192.e5. doi: 10.1016/j.stem.2018.06.002. Epub 2018 Jun 28.

Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity.

Author information

1
Department of Medicine, Division of Regenerative Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
2
Department of Medicine, University of Minnesota Minneapolis, Minneapolis, MN 55455, USA.
3
Department of Pediatrics, Masonic Cancer Center and Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55455, USA.
4
Department of Medicine, Division of Regenerative Medicine, Moores Cancer Center and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: dskaufman@ucsd.edu.

Abstract

Chimeric antigen receptors (CARs) significantly enhance the anti-tumor activity of immune effector cells. Although most studies have evaluated CAR expression in T cells, here we evaluate different CAR constructs that improve natural killer (NK) cell-mediated killing. We identified a CAR containing the transmembrane domain of NKG2D, the 2B4 co-stimulatory domain, and the CD3ζ signaling domain to mediate strong antigen-specific NK cell signaling. NK cells derived from human iPSCs that express this CAR (NK-CAR-iPSC-NK cells) have a typical NK cell phenotype and demonstrate improved anti-tumor activity compared with T-CAR-expressing iPSC-derived NK cells (T-CAR-iPSC-NK cells) and non-CAR-expressing cells. In an ovarian cancer xenograft model, NK-CAR-iPSC-NK cells significantly inhibited tumor growth and prolonged survival compared with PB-NK cells, iPSC-NK cells, or T-CAR-iPSC-NK cells. Additionally, NK-CAR-iPSC-NK cells demonstrate in vivo activity similar to that of T-CAR-expressing T cells, although with less toxicity. These NK-CAR-iPSC-NK cells now provide standardized, targeted "off-the-shelf" lymphocytes for anti-cancer immunotherapy.

KEYWORDS:

chimeric antigen receptors; iPSCs; immunotherapy; natural killer cells; ovarian cancer

PMID:
30082067
PMCID:
PMC6084450
[Available on 2019-08-02]
DOI:
10.1016/j.stem.2018.06.002

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