On-target off-tumor toxicity of claudin18.2-directed CAR-T cells in preclinical models

Filippo Birocchi, Antonio J. Almazan, Aiyana Parker, Amanda A. Bouffard, Sadie Goncalves, Christopher Kelly, Jessica Frank, Mark B. Leick, Nicholas J. Haradhvala, Shaw Kagawa, Gad Getz, Giulia Escobar, Diego Salas-Benito, Adele Mucci, Trisha R. Berger and Marcela V. Maus ()
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Filippo Birocchi: Massachusetts General Hospital
Antonio J. Almazan: Massachusetts General Hospital
Aiyana Parker: Massachusetts General Hospital
Amanda A. Bouffard: Massachusetts General Hospital
Sadie Goncalves: Massachusetts General Hospital
Christopher Kelly: Massachusetts General Hospital
Jessica Frank: Massachusetts General Hospital
Mark B. Leick: Massachusetts General Hospital
Nicholas J. Haradhvala: Massachusetts General Hospital
Shaw Kagawa: Broad Institute of Harvard University and Massachusetts Institute of Technology
Gad Getz: Massachusetts General Hospital
Giulia Escobar: Massachusetts General Hospital
Diego Salas-Benito: Massachusetts General Hospital
Adele Mucci: Massachusetts General Hospital
Trisha R. Berger: Massachusetts General Hospital
Marcela V. Maus: Massachusetts General Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Claudin 18.2 (CLDN18.2)-targeted CAR-T cell therapies have shown promising clinical efficacy in gastric cancer. However, early-phase trials have reported gastrointestinal adverse events due to on-target off-tumor recognition of CLDN18.2 in the gastric mucosa. By leveraging shared CLDN18.2 epitopes and expression in humans and mice, we establish an in vivo model that replicates the on-target off-tumor toxicity of CLDN18.2 CAR-T. Our findings confirm that this toxicity is independent of the CAR construct’s design, co-stimulatory domain, and tumor model. Additionally, we demonstrate the utility of this model in testing strategies to mitigate on-target toxicity, such as Boolean-logic AND-gate approaches. Our results offer insights into the use of mouse models that recapitulate on-target off-tumor toxicities, with the caveat that although we are often concerned that models will undercall toxicities in humans, they may also overcall the incidence and severity of toxicities, prematurely discarding promising therapeutic agents from further clinical development.

Date: 2025
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DOI: 10.1038/s41467-025-61858-z

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