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

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

Abstract 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 evaluat...

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Main Authors: 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
Format: Article
Language:English
Published: Nature Portfolio 2025-08-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-025-61427-4
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Summary:Abstract 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.
ISSN:2041-1723

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