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<p>Chimeric antigen receptor (CAR)-T cell efficacy in solid tumours is limited due in part to the immunosuppressive tumour microenvironment (TME). To improve antitumour responses, we hypothesized that enabling CAR-T cells to secrete bifunctional fusion proteins consisting of a cytokine modifier such as TGFβ<sup>trap</sup>, IL-15 or IL-12, combined with an immune checkpoint inhibitor such as αPD-L1, would provide tumour-localized immunomodulation to improve CAR-T cell functionality. Here we engineer CAR-T cells to secrete TGFβ<sup>trap</sup>, IL-15 or IL-12 molecules fused to αPD-L1 scFv and assess in vitro functionality and in vivo safety and efficacy in prostate and ovarian cancer models. CAR-T cells engineered with αPD-L1–IL-12 are superior in safety and efficacy compared with CAR-T cells alone and those engineered with αPD-L1 fused with TGFβ<sup>trap</sup> or IL-15. Further, αPD-L1–IL-12 engineered CAR-T cells improve T cell trafficking and tumour infiltration, and localize IFNγ production, TME modulation and antitumour responses, with reduced systemic inflammation-associated toxicities. We believe our αPD-L1–IL-12 engineering strategy presents an opportunity to improve CAR-T cell clinical efficacy and safety across multiple solid tumour types.</p>

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Solid tumour CAR-T cells engineered with fusion proteins targeting PD-L1 for localized IL-12 delivery

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月1日

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  • John P. Murad,
  • Lea Christian,
  • Reginaldo Rosa,
  • Yuwei Ren,
  • Alyssa J. Buckley,
  • Eric Hee Jun Lee,
  • Lupita S. Lopez,
  • Anthony K. Park,
  • Jason Yang,
  • Yukiko Yamaguchi,
  • Candi Trac,
  • Lauren N. Adkins,
  • Wen-Chung Chang,
  • Catalina Martinez,
  • Carl H. June,
  • Stephen J. Forman,
  • Jun Ishihara,
  • John K. Lee,
  • Lawrence A. Stern,
  • Saul J. Priceman

摘要

Chimeric antigen receptor (CAR)-T cell efficacy in solid tumours is limited due in part to the immunosuppressive tumour microenvironment (TME). To improve antitumour responses, we hypothesized that enabling CAR-T cells to secrete bifunctional fusion proteins consisting of a cytokine modifier such as TGFβtrap, IL-15 or IL-12, combined with an immune checkpoint inhibitor such as αPD-L1, would provide tumour-localized immunomodulation to improve CAR-T cell functionality. Here we engineer CAR-T cells to secrete TGFβtrap, IL-15 or IL-12 molecules fused to αPD-L1 scFv and assess in vitro functionality and in vivo safety and efficacy in prostate and ovarian cancer models. CAR-T cells engineered with αPD-L1–IL-12 are superior in safety and efficacy compared with CAR-T cells alone and those engineered with αPD-L1 fused with TGFβtrap or IL-15. Further, αPD-L1–IL-12 engineered CAR-T cells improve T cell trafficking and tumour infiltration, and localize IFNγ production, TME modulation and antitumour responses, with reduced systemic inflammation-associated toxicities. We believe our αPD-L1–IL-12 engineering strategy presents an opportunity to improve CAR-T cell clinical efficacy and safety across multiple solid tumour types.