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

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 Blank, Femke Ham, Brenna R. ‘t Veld, Gabrielle Ferry, Jonathan Fisher, Debarati Shome, Reza Nadafi, Israrul H. Ansari, Rogier Reijmers, Stefano Giuliani, Paul Sondel, Laura K. Donovan, Louis Chesler, Molenaar, Jarno Drost, Anne C. Rios, Kerry Chester, Judith Wienke () and John Anderson ()
Additional contact information
Marta Barisa: University College London
Henrike P. Muller: University College London
Elisa Zappa: Princess Máxima Center for Pediatric Oncology
Rivani Shah: University College London
Juliane L. Buhl: Princess Máxima Center for Pediatric Oncology
Benjamin Draper: University College London
Courtney Himsworth: University College London
Chantelle Bowers: University College London
Sophie Munnings-Tomes: University College London
Marilena Nicolaidou: University College London
Sonia Morlando: University College London
Kathleen Birley: University College London
Clara Leboreiro-Babe: University College London
Alice Vitali: University College London
Laura Privitera: University College London
Kyle O’Sullivan: University College London
Ailsa Greppi: University College London
Magdalena Buschhaus: Lumicks
Mario Barrera Román: Princess Máxima Center for Pediatric Oncology
Sam Blank: Princess Máxima Center for Pediatric Oncology
Femke Ham: Princess Máxima Center for Pediatric Oncology
Brenna R. ‘t Veld: Princess Máxima Center for Pediatric Oncology
Gabrielle Ferry: University College London
Jonathan Fisher: University College London
Debarati Shome: Lumicks
Reza Nadafi: Lumicks
Israrul H. Ansari: University of Wisconsin-Madison
Rogier Reijmers: Lumicks
Stefano Giuliani: University College London
Paul Sondel: University of Wisconsin-Madison
Laura K. Donovan: University College London
Louis Chesler: University College London
Molenaar: Princess Máxima Center for Pediatric Oncology
Jarno Drost: Princess Máxima Center for Pediatric Oncology
Anne C. Rios: Princess Máxima Center for Pediatric Oncology
Kerry Chester: The Institute of Cancer Research
Judith Wienke: Princess Máxima Center for Pediatric Oncology
John Anderson: University College London

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-61427-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-61427-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-61427-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().