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

  • Cell Stem Cell. 2025 Jul 3;32(7):1087-1101.e4. doi: 10.1016/j.stem.2025.05.007.
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
  • 1. Fate Therapeutics, Inc., San Diego, CA, USA. Electronic address: [email protected].
  • 2. Fate Therapeutics, Inc., San Diego, CA, USA.
  • 3. Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Miyagi, Japan.
  • 4. Minase Research Institute, Ono Pharmaceutical Co., Ltd., Osaka, Japan.
  • 5. Institute for Protein Research, Osaka University, 3-2, Yamadaoka, Suita 565-0871, Osaka, Japan.
  • 6. Fate Therapeutics, Inc., San Diego, CA, USA. Electronic address: [email protected].
PMID: 40472844 DOI: 10.1016/j.stem.2025.05.007
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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