Barisa Marta, Muller Henrike P, Zappa Elisa, Shah Rivani, Buhl Juliane L, Draper Benjamin, Himsworth Courtney, Bowers Chantelle, Munnings-Tomes Sophie, Nicolaidou Marilena, Morlando Sonia, Birley Kathleen, Leboreiro-Babe Clara, Vitali Alice, Privitera Laura, O'Sullivan Kyle, Greppi Ailsa, Buschhaus Magdalena, Román Mario Barrera, de Blank Sam, van den Ham Femke, van 't Veld Brenna R, Ferry Gabrielle, Fisher Jonathan, Shome Debarati, Nadafi Reza, Ansari Israrul H, Reijmers Rogier, Giuliani Stefano, Sondel Paul, Donovan Laura K, Chesler Louis, Drost Jarno, Rios Anne C, Chester Kerry, Wienke Judith, Anderson John
Great Ormond Street Institute of Child Health, University College London, London, UK.
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Nat Commun. 2025 Aug 5;16(1):7196. doi: 10.1038/s41467-025-61427-4.
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.
用于实体癌的嵌合抗原受体T细胞（CAR-T）疗法，在与表达抗原的靶细胞相互作用后，因在肿瘤微环境中的扩增受限和存活时间有限而受到影响。以具有广泛临床适用性的B7H3作为模型抗原，我们评估了三种临床候选结合物的抗体/抗原亲和力与以下三个特征之间的关系：细胞亲和力、类肿瘤再刺激试验中持续细胞毒性的持续时间以及体内抗肿瘤反应。接下来，使用BEHAV3D视频显微镜在单细胞分辨率下评估CAR-T细胞与肿瘤细胞的相互作用。这些数据与CAR-T/肿瘤细胞相互作用的阈值亲和力和靶细胞B7H3表达水平一致，其中增强的功能以更长的累积CD8 CAR-T/肿瘤靶标相互作用时间、CAR-T细胞扩增和持续的肿瘤控制为特征。较低的检查点受体表达与增强的抗肿瘤功能无关。这些结果为设计用于抗原低表达细胞靶向的抗B7H3 CAR-T细胞以及避免抗原低表达肿瘤复发提供了进一步的见解。
