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<p>Chimeric Antigen receptor T cell (CAR-T) treatments for solid cancers have been compromised by limited expansion and survival in the tumor microenvironment following interaction with antigen-expressing target cells. Using B7H3 as a model antigen with broad clinical applicability, we evaluate the relationship between the antibody/antigen affinity of three clinical candidate binders and the three following characteristics: cellular avidity, duration of sustained cytotoxicity in tumoroid re-stimulation assays, and in vivo anti-tumoral responses. Next, BEHAV3D video&#xa0;microscopy is used to assess CAR-T cell interaction with tumor cells at single cell resolution. These data are consistent with a threshold avidity of CAR-T / tumor cell interaction and target cell B7H3 expression level, where enhanced functionality is characterized by longer cumulative CD8<sup>+</sup> CAR-T / tumor target interaction times, CAR-T cell expansion and sustained tumor control. Lower checkpoint receptor expression does not correlate with enhanced anti-tumor function. These results provide further insights into design of anti-B7H3 CAR-T cells for antigen-dim cell targeting, and avoidance of antigen-dim tumor relapse.</p>

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Functional avidity of anti-B7H3 CAR-T constructs predicts antigen density thresholds for triggering effector function

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月5日

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  • Marta Barisa,
  • Henrike P. Muller,
  • Elisa Zappa,
  • Rivani Shah,
  • Juliane L. Buhl,
  • Benjamin Draper,
  • Courtney Himsworth,
  • Chantelle Bowers,
  • Sophie Munnings-Tomes,
  • Marilena Nicolaidou,
  • Sonia Morlando,
  • Kathleen Birley,
  • Clara Leboreiro-Babe,
  • Alice Vitali,
  • Laura Privitera,
  • Kyle O’Sullivan,
  • Ailsa Greppi,
  • Magdalena Buschhaus,
  • Mario Barrera Román,
  • Sam de Blank,
  • Femke van den Ham,
  • Brenna R. van ‘t Veld,
  • Gabrielle Ferry,
  • Jonathan Fisher,
  • Debarati Shome,
  • Reza Nadafi,
  • Israrul H. Ansari,
  • Rogier Reijmers,
  • Stefano Giuliani,
  • Paul Sondel,
  • Laura K. Donovan,
  • Louis Chesler,
  • Jan Molenaar,
  • Jarno Drost,
  • Anne C. Rios,
  • Kerry Chester,
  • Judith Wienke,
  • John Anderson

摘要

Chimeric Antigen receptor T cell (CAR-T) treatments for solid cancers have been compromised by limited expansion and survival in the tumor microenvironment following interaction with antigen-expressing target cells. Using B7H3 as a model antigen with broad clinical applicability, we evaluate the relationship between the antibody/antigen affinity of three clinical candidate binders and the three following characteristics: cellular avidity, duration of sustained cytotoxicity in tumoroid re-stimulation assays, and in vivo anti-tumoral responses. Next, BEHAV3D video microscopy is used to assess CAR-T cell interaction with tumor cells at single cell resolution. These data are consistent with a threshold avidity of CAR-T / tumor cell interaction and target cell B7H3 expression level, where enhanced functionality is characterized by longer cumulative CD8+ CAR-T / tumor target interaction times, CAR-T cell expansion and sustained tumor control. Lower checkpoint receptor expression does not correlate with enhanced anti-tumor function. These results provide further insights into design of anti-B7H3 CAR-T cells for antigen-dim cell targeting, and avoidance of antigen-dim tumor relapse.