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<p>Recent studies suggest that Chimeric Antigen Receptor (CAR) binding affinity to its ligand affects CAR-T-cell functionality. Affinity engineering towards lower binding strengths might mitigate therapeutic side effects arising from intense CAR-T-cell activation as well as tumor relapse due to antigen-escape or limited persistence of CAR-T cells during sustained activation via high-affinity receptors. Here we characterize a broad range of CARs with varying affinities to the same target epitope and leverage the insights we gain to design a combined high- and low-affinity CAR product. While CAR affinity impacts in vitro functionality minimally, it strongly correlates with tumor control in vivo. Low-affinity binders cause only mild cytokine release syndrome (CRS) in humanized mouse models at the expense of anti-tumour efficiency. In mixtures with low-affinity CARs, high-affinity CARs maintain strong functionality while showing reduced signs of exhaustion and monocyte-induced cytokine production, compared to high-affinity CAR-T cells alone. In long term in vitro and in vivo settings, low-affinity CAR-T cells dominate over time, proving more resilience to chronic antigen exposure. Overall, our findings demonstrate that affinity combination represents a promising strategy to generate more effective CAR-T-cell products with an improved therapeutic index, beyond affinity engineering alone.</p>

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Balancing the efficacy and safety of chimeric antigen receptor T-cell therapy by affinity combination

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月10日

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  • Linda Warmuth,
  • Sarah Dötsch,
  • Manuel Trebo,
  • Sarah Bellucci,
  • Sophia Engels,
  • Rafael Valdivia Manrique,
  • Karl Moukarzel,
  • Julius M. Schütz,
  • Monika Hammel,
  • Adrian Straub,
  • Sabrina Wagner,
  • Anna Hochholzer,
  • Ciro Salinno,
  • Jacqueline Seigner,
  • Charlotte U. Zajc,
  • Georg P. Schmidt,
  • Josefine Michael,
  • Thomas Nerreter,
  • Michael Hudecek,
  • Michael W. Traxlmayr,
  • Monica Casucci,
  • Stanley R. Riddell,
  • Mateusz P. Poltorak,
  • Dirk H. Busch,
  • Elvira D’Ippolito

摘要

Recent studies suggest that Chimeric Antigen Receptor (CAR) binding affinity to its ligand affects CAR-T-cell functionality. Affinity engineering towards lower binding strengths might mitigate therapeutic side effects arising from intense CAR-T-cell activation as well as tumor relapse due to antigen-escape or limited persistence of CAR-T cells during sustained activation via high-affinity receptors. Here we characterize a broad range of CARs with varying affinities to the same target epitope and leverage the insights we gain to design a combined high- and low-affinity CAR product. While CAR affinity impacts in vitro functionality minimally, it strongly correlates with tumor control in vivo. Low-affinity binders cause only mild cytokine release syndrome (CRS) in humanized mouse models at the expense of anti-tumour efficiency. In mixtures with low-affinity CARs, high-affinity CARs maintain strong functionality while showing reduced signs of exhaustion and monocyte-induced cytokine production, compared to high-affinity CAR-T cells alone. In long term in vitro and in vivo settings, low-affinity CAR-T cells dominate over time, proving more resilience to chronic antigen exposure. Overall, our findings demonstrate that affinity combination represents a promising strategy to generate more effective CAR-T-cell products with an improved therapeutic index, beyond affinity engineering alone.