Human iPSC-derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-Tumor Activity

By Ye Li, D. Hermanson, Branden S. Moriarity, D. Kaufman. Cell Stem Cell, 2018

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Summary Chimeric antigen receptors (CARs) significantly enhance anti-tumor activity of immune effector cells. While 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 to T-CAR expressing iPSC-derived NK cells (T-CAR-iPSC-NK cells) and non-CAR expressing cells. Using an ovarian cancer xenograft model, NK-CAR-iPSC-NK cells significantly inhibited tumor growth and prolonged survival compared to PB-NK cells, iPSC-NK cells, or T-CAR-iPSC-NK cells. Additionally, NK-CAR-iPSC-NK cells demonstrate similar in vivo activity as T-CAR-expressing T cells, though with less toxicity. These NK-CAR-iPSC-NK cells now provide standardized, targeted “off the shelf” lymphocytes for anti-cancer immunotherapy.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/b0a61b6a198fa3e27d120e51a090aa7f3c89d3ba