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. Natural killer (NK) cells are a key part of the immune system's ability to mediate anti-cancer activity. Li et al. utilize human iPSCs to produce NK cells with novel chimeric antigen receptors that specifically target cancer cells in an antigen-specific manner to improve survival in an ovarian cancer xenograft model.
Bibliographical noteFunding Information:
We thank Jacqueline K. Le and Natalie K. Wolf for technical assistance. The serous epithelial ovarian tumor cell lines MA-148 and A1847 were kindly provided by Sundaram Ramakrishnan (University of Minnesota) and Reuben Harris (University of Minnesota), respectively. We appreciate helpful discussions with Dr. Bob Valamehr and colleagues at Fate Therapeutics. We gratefully acknowledge support and assistance from the Sanford Consortium for Regenerative Medicine Flow Cytometry and Histology cores and pathologist Dr. Kent Osborn. These studies were supported by funding from the NIH ( R01CA203348 and U01 CA217885 ), CIRM ( DISC2-09615 ), and Fate Therapeutics (to D.S.K.).
D.S.K. has research funding from and serves as a consultant for Fate Therapeutics. D.S.K., D.L.H., and B.S.M. have filed a patent related to these studies.
- chimeric antigen receptors
- natural killer cells
- ovarian cancer