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
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 evaluated the relationship between the antibody/antigen affinity of three clinical candidate binders and the three following functional characteristics: functional avidity, prolonged cytotoxicity in tumoroid re-stimulation assays, and in vivo anti-tumoral responses. BEHAV3D video-microscopy assessed distinct CAR-T cell behaviors at single cell resolution. T cell exhaustion did not dictate effector function. Rather, we demonstrated a threshold avidity of CAR-T / tumor cell interaction, characterized by longer cumulative CD8+ CAR-T / tumor target interaction times, and required for adequate CAR-T cell expansion to result in sustained tumor control upon re-challenge. These results provide new insights into design of CAR-T cells for antigen-dim cell targeting, and avoidance of antigen-dim tumor relapse.
Buhl Juliane、Rios Anne C.、Greppi Ailsa、Barisa Marta、Zappa Elisa、Muller Henrike、Nicolaidou Marilena、Morlando Sonia、Leboreiro-Babe Clara、Vitali Alice、Privitera Laura、O'Sullivan Kyle、van 't Veld Brenna R.、Ferry Gabrielle、Donovan Laura K.、Molenaar Jan J.、Drost Jarno、Chester Kerry、van den Ham Femke、Wienke Judith、Birley Kathleen、Buschhaus Magdalena、Anderson John、Draper Benjamin、Barrera Roman Mario、Chesler Louis、Munnings-Tomes Sophie、Bowers Chantelle、Shah Rivani、de Blank Sam、Himsworth Courtney
肿瘤学生物科学研究方法、生物科学研究技术基础医学
Buhl Juliane,Rios Anne C.,Greppi Ailsa,Barisa Marta,Zappa Elisa,Muller Henrike,Nicolaidou Marilena,Morlando Sonia,Leboreiro-Babe Clara,Vitali Alice,Privitera Laura,O'Sullivan Kyle,van 't Veld Brenna R.,Ferry Gabrielle,Donovan Laura K.,Molenaar Jan J.,Drost Jarno,Chester Kerry,van den Ham Femke,Wienke Judith,Birley Kathleen,Buschhaus Magdalena,Anderson John,Draper Benjamin,Barrera Roman Mario,Chesler Louis,Munnings-Tomes Sophie,Bowers Chantelle,Shah Rivani,de Blank Sam,Himsworth Courtney.Functional avidity of anti-B7H3 CAR-T constructs predicts antigen density thresholds for triggering effector function[EB/OL].(2025-03-28)[2025-06-28].https://www.biorxiv.org/content/10.1101/2024.02.19.580939.点此复制
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