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Preprint WatchModerateJuly 29th, 2026

Safety profiling of CAR-T cells using an organotypic human tissue platform

Machado, A.; Birsen, G.; Rajnpreht, I.; Furtado Peter, I.; Colell, S.; Marzal, B.; Fredon, M.; Ziegler-Martin, K.; Martinez Bedoya, D.; Fumagalli, M.; Vimeux, L.; Davanture, S.; Melchiore, F.; Thomas, A.; Collet, M.; Fremand, X.; Burroni, B.; Laugel, B.; Lupo-Mansuet, A.; Prieto, M.; Damotte, D.; Le Doussal, J.-M.; Luu, M.; Dutoit, V.; Garnache-Ottou, F.; Guedan, S.; Migliorini, D.; Donnadieu, E.

CAR-T cells directed at EGFR, HER2 and mesothelin induced inflammatory and cytotoxic responses in intact healthy human lung tissue, while CD19 CAR-T cells remained inactive, and on-target off-tumour toxicity was not predictable from antigen abundance alone but depended on CAR affinity, inflammatory context, antigen accessibility and effector-cell dose.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint reports that HER2-directed CAR-T cells trigger inflammatory and cytotoxic responses in intact healthy human lung tissue, and that on-target off-tumour toxicity cannot be predicted from antigen abundance alone. Claidex holds two ERBB2 post-mortems that bear on the same problem from the small-molecule and antibody-drug-conjugate side. In poziotinib-erbb2-her2-exon20-nsclc-zenith20-phase2-translational-mismatch, preclinical potency against HER2 exon 20 outran the therapeutic window in patients, a translational mismatch rather than a target-validity failure. In xmt-2056-erbb2-her2-sting-agonist-adc-phase1-strategic-discontinuation, a HER2-directed STING-agonist conjugate was discontinued in Phase 1. The common thread is that HER2 expression on normal tissue sets the ceiling for every modality aimed at it, and the platform described here would have provided a preclinical readout of exactly the constraint those programmes met in the clinic. Teams designing HER2-directed cell therapies should treat this as a reason to generate tissue-level safety data before dose escalation rather than as evidence that the target is unusable.

Abstract excerpt

CAR-T-cell-associated on-target off-tumor (OTOT) toxicity represents a major safety concern, as recognition of target antigens on healthy tissues can trigger severe and potentially life-threatening complications. Predicting OTOT toxicity remains a challenge because current preclinical models fail to capture the complexity of native human tissues. Here, we developed a human organotypic tissue platform that enables functional assessment of CAR-T-cell activity in intact human tissues across organ-specific and inflammatory contexts. Using a panel of clinically relevant CAR-T-cell products with known OTOT toxicities, we demonstrate that the platform faithfully recapitulates clinically observed tissue-specific toxicity profiles. CAR-T cells targeting EGFR, HER2, and mesothelin induced inflammatory and cytotoxic responses in healthy human lung tissue, whereas CD19 CAR-T cells remained inactive. We further show that OTOT toxicity cannot be reliably predicted from antigen abundance alone but instead results from the integration of multiple target-dependent determinants, including CAR affinity, inflammatory context, antigen accessibility, and effector-cell dose. The platform also enables quantitative assessment of inflammatory and cytotoxic responses and supports evaluation of pharmacological and CAR design-based strategies to mitigate toxicity. Together, this work establishes the first human organotypic platform for functional modeling of CAR-T-cell-associated OTOT toxicity, providing a clinically relevant framework for preclinical safety evaluation and the rational development of safer engineered cell therapies.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.