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

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

doi:10.7554/eLife.49392

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

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

Research output: Contribution to journal › Article

3 Citations (Scopus)

Abstract

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.

Original language	English
Article number	e49392
Journal	eLife
Volume	9
DOIs	https://doi.org/10.7554/eLife.49392
Publication status	Published - 2020 Mar

ASJC Scopus subject areas

Neuroscience(all)
Immunology and Microbiology(all)
Biochemistry, Genetics and Molecular Biology(all)

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Kato, D., Yaguchi, T., Iwata, T., Katoh, Y., Morii, K., Tsubota, K., Takise, Y., Tamiya, M., Kamada, H., Akiba, H., Tsumoto, K., Serada, S., Naka, T., Nishimura, R., Nakagawa, T., & Kawakami, Y. (2020). GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 ab. eLife, 9, [e49392]. https://doi.org/10.7554/eLife.49392

GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 ab. / Kato, Daiki; Yaguchi, Tomonori; Iwata, Takashi; Katoh, Yuki; Morii, Kenji; Tsubota, Kinya; Takise, Yoshiaki; Tamiya, Masaki; Kamada, Haruhiko; Akiba, Hiroki; Tsumoto, Kouhei; Serada, Satoshi; Naka, Tetsuji; Nishimura, Ryohei; Nakagawa, Takayuki; Kawakami, Yutaka.

In: eLife, Vol. 9, e49392, 03.2020.

Research output: Contribution to journal › Article

Kato, Daiki ; Yaguchi, Tomonori ; Iwata, Takashi ; Katoh, Yuki ; Morii, Kenji ; Tsubota, Kinya ; Takise, Yoshiaki ; Tamiya, Masaki ; Kamada, Haruhiko ; Akiba, Hiroki ; Tsumoto, Kouhei ; Serada, Satoshi ; Naka, Tetsuji ; Nishimura, Ryohei ; Nakagawa, Takayuki ; Kawakami, Yutaka. / GPC1 specific CAR-T cells eradicate established solid tumor without adverse effects and synergize with anti-PD-1 ab. In: eLife. 2020 ; Vol. 9.

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abstract = "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.",

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AU - Serada, Satoshi

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