GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 Ab

eLife

Hiroki Akiba¹  Haruhiko Kamada¹  Kouhei Tsumoto¹  Satoshi Serada²  Tetsuji Naka²  Tomonori Yaguchi³  Yuki Katoh³  Yoshiaki Takise³  Masaki Tamiya³  Kenji Morii³  Takashi Iwata⁴  Kinya Tsubota⁵  Yutaka Kawakami⁶  Daiki Kato⁷  Takayuki Nakagawa⁸  Ryohei Nishimura⁸ 

[1] Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Tokyo, Japan;Center for Intractable Immune Disease, Kochi Medical School, Kochi University, Kochi, Japan;Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan;Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan;Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan;Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan;Department of Ophthalmology, Tokyo Medical University, Tokyo, Japan;Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan;Department of immunology, School of Medicine, International University of Health and Welfare, Tokyo, Japan;Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, Japan;Laboratory of Veterinary Surgery, Graduate school of agricultural and life sciences, The University of Tokyo, Tokyo, Japan;Laboratory of Veterinary Surgery, Graduate school of agricultural and life sciences, The University of Tokyo, Tokyo, Japan;

关键词: adverse effects;    anti-PD-1 Ab;    combination immunotherapy;    CAR-T cells;    solid tumor;    Human;    Mouse;   

DOI  :  10.7554/eLife.49392

来源: publisher

【 摘 要 】

Current xenogeneic mouse models cannot evaluate on-target off-tumor adverse effect, hindering the development of chimeric antigen receptor (CAR) T cell therapies for solid tumors, due to limited human/mouse cross-reactivity of antibodies used in CAR and sever graft-versus-host disease induced by administered human T cells. We have evaluated safety and antitumor efficacy of CAR-T cells targeting glypican-1 (GPC1) overexpressed in various solid tumors. GPC1-specific human and murine CAR-T cells generated from our original anti-human/mouse GPC1 antibody showed strong antitumor effects in xenogeneic and syngeneic mouse models, respectively. Importantly, the murine CAR-T cells enhanced endogenous T cell responses against a non-GPC1 tumor antigen through the mechanism of antigen-spreading and showed synergistic antitumor effects with anti-PD-1 antibody without any adverse effects in syngeneic models. Our study shows the potential of GPC1 as a CAR-T cell target for solid tumors and the importance of syngeneic and xenogeneic models for evaluating their safety and efficacy.

【 授权许可】

CC BY