Barisa, Marta;
Muller, Henrike P;
Zappa, Elisa;
Shah, Rivani;
Buhl, Juliane L;
Draper, Benjamin;
Himsworth, Courtney;
... Anderson, John; + view all
(2025)
Functional avidity of anti-B7H3 CAR-T constructs predicts antigen density thresholds for triggering effector function.
Nature Communications
, 16
, Article 7196. 10.1038/s41467-025-61427-4.
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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.
| Type: | Article |
|---|---|
| Title: | Functional avidity of anti-B7H3 CAR-T constructs predicts antigen density thresholds for triggering effector function |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41467-025-61427-4 |
| Publisher version: | https://doi.org/10.1038/s41467-025-61427-4 |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10217648 |
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