Cell Stem Cell
Volume 23, Issue 2, 2 August 2018, Pages 181-192.e5
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Article
Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity

https://doi.org/10.1016/j.stem.2018.06.002Get rights and content
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Highlights

  • Human iPSC-derived NK cells provide an “off-the-shelf” resource for cancer therapy

  • New CAR constructs optimize targeted anti-tumor activity of iPSC-derived NK cells

  • Optimized NK-CAR-expressing iPSC-NK cells activate specific intracellular signals

  • NK-CAR iPSC-NK cells demonstrate increased in vivo expansion and improved activity

Summary

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

natural killer cells
chimeric antigen receptors
iPSCs
immunotherapy
ovarian cancer

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Present address: B-MoGen Biotechnologies, Inc., Minneapolis, MN, USA

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