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

• DOI: 10.7554/elife.49392
• Publication Date: 2020-03-31T00:00:22Z
• Authors: Daiki Kato; Tomonori Yaguchi; Takashi Iwata; Yuki Katoh; Kenji Morii; Kinya Tsubota; Yoshiaki Takise; Masaki Tamiya; Haruhiko Kamada; Hiroki Akiba; Kouhei Tsumoto; Satoshi Serada; Tetsuji Naka; Ryohei Nishimura; Takayuki Nakagawa; Yutaka Kawakami
• Keywords: Male; 0301 basic medicine; CAR-T cells; QH301-705.5; Science; T-Lymphocytes; anti-PD-1 Ab; Programmed Cell Death 1 Receptor; Receptors, Antigen, T-Cell; Immunotherapy, Adoptive; Cell Line; Mice; 03 medical and health sciences; Glypicans; Cell Line, Tumor; Animals; Humans; Biology (General); Cancer Biology; Receptors, Chimeric Antigen; Q; R; Xenograft Model Antitumor Assays; 3. Good health; Mice, Inbred C57BL; combination immunotherapy; adverse effects; Medicine; solid tumor; Female

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.