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. 2025 Jul 3;32(7):1087-1101.e4.
doi: 10.1016/j.stem.2025.05.007. Epub 2025 Jun 4.

Preferential tumor targeting of HER2 by iPSC-derived CAR T cells engineered to overcome multiple barriers to solid tumor efficacy

Martin P Hosking  1 , Soheila Shirinbak  2 , Kyla Omilusik  2 , Shilpi Chandra  2 , Mika K Kaneko  3 , Angela Gentile  2 , Susumu Yamamoto  4 , Bishwas Shrestha  2 , Joy Grant  2 , Megan Boyett  2 , Demetrio Cardenas  2 , Hannah Keegan  2 , Samad Ibitokou  2 , Carolina Pavon  2 , Takahiro Mizoguchi  4 , Tatsuya Ihara  4 , Daisuke Nakayama  4 , Ramzey Abujarour  2 , Tom T Lee  2 , Raedun Clarke  2 , Jode Goodridge  2 , Eigen Peralta  2 , Tatsuo Maeda  4 , Junichi Takagi  5 , Takao Arimori  5 , Yukinari Kato  3 , Bahram Valamehr  6
Affiliations

Preferential tumor targeting of HER2 by iPSC-derived CAR T cells engineered to overcome multiple barriers to solid tumor efficacy

Martin P Hosking et al. Cell Stem Cell. .

Abstract

Chimeric antigen receptor (CAR) T cell therapies in solid tumors have been limited by on-target, off-tumor toxicity, antigen heterogeneity, and an inability to simultaneously overcome multiple diverse resistance mechanisms within the tumor microenvironment that attenuate anti-tumor activity. Here, we describe an induced pluripotent stem cell (iPSC)-derived CAR T cell that combines a human epidermal growth factor receptor 2 (HER2)-targeting CAR-differentially recognizing tumor from normal cells and enabling detection of both truncated and misfolded HER2-with multiplex editing designed to address and overcome obstacles to maximize efficacy in solid tumor indications. The iPSC-derived, HER2-directed CAR T cells maintained potent HER2-specific anti-tumor activity in both in vitro and in vivo settings, with limited cytolytic targeting of HER2+ normal targets. Combination with therapeutic antibodies enabled comprehensive multi-antigen targeting through both the CAR and a high-affinity, non-cleavable CD16a Fc receptor. Additionally, specific engineering of interleukin (IL)-7R-fusion, transforming growth factor β (TGF-β)-IL-18R, and CXCR2 enabled sustained persistence, resistance to TGF-β-mediated suppression, and specific migration to the tumor.

Keywords: CAR T; HER2; TGF-β; antibody-dependent cellular cytotoxicity; iPSC; solid tumor; trafficking.

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Conflict of interest statement

Declaration of interests M.P.H., S.S., K.O., S.C., A.G., B.S., J. Grant, M.B., D.C., H.K., S.I., C.P., R.A., T.T.L., R.C., J. Goodridge, E.P., and B.V. are employees of Fate Therapeutics Inc. S.Y., T. Mizoguchi, T.I., D.N., and T. Maeda are employees of Ono Pharmaceutical Co., Ltd. Y.K. has received research funding from Ono Pharmaceutical Co., Ltd. Patent applications related to this work have been filed.