[PDF][PDF] Human iPSC-derived natural killer cells engineered with chimeric antigen receptors enhance anti-tumor activity

Y Li, DL Hermanson, BS Moriarity, DS Kaufman - Cell stem cell, 2018 - cell.com
Y Li, DL Hermanson, BS Moriarity, DS Kaufman
Cell stem cell, 2018cell.com
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 …
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.
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