ArticleNature communications2025
On-target off-tumor toxicity of claudin18.2-directed CAR-T cells in preclinical models.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
12 citing papers in PubMed.
- Barriers and Blueprints: Next-Generation Engineering Strategies for CAR-T Cell Therapy in Gastrointestinal Tumors.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Clinical implications of zolbetuximab-associated hypoalbuminemia in CLDN18.2-positive gastric or gastroesophageal junction cancer.ESMO gastrointestinal oncology · 2026Article
- From barrier to trigger: leveraging tumor hypoxia for precise control of CAR-T cell activity.Molecular biology reports · 2026Review
- Spatial Regulation of CAR Signaling Enables Logic-Gated Activity.bioRxiv : the preprint server for biology · 2026Article
- Immuno-cytotoxic convergence: integrating antibody‒drug conjugates and immunofusion proteins to overcome resistance in gastrointestinal cancers.Journal of hematology & oncology · 2026Review
- Translational advances in gastric cancer: integrating biomarkers, novel therapies, and microenvironment remodeling in 2025.Translational cancer research · 2026Review
- Nanoparticles-enhanced CAR-T cell therapy: current advances and future directions.Biomarker research · 2026Review
- CAR-T cell therapy for pancreatic cancer: Translating emerging targets and dual-targeting strategies from solid tumors.Frontiers in immunology · 2026Review
- Resistance mechanisms and countermeasures in CLDN18.2-positive tumors: from molecular networks to clinical practice.Frontiers in oncology · 2026Review
- Engineering CAR-T cells for solid tumors: overcoming antigenic, trafficking, and microenvironmental barriers.Frontiers in immunology · 2026Review
- Modeling and addressing on-target/off-tumor toxicity of claudin 18.2 targeted immunotherapies.Nature communications · 2025Article
- Multi-Omics-Enabled Precision Strategies for Overcoming CAR-T Therapy Limitations in Gastrointestinal Malignancies.BioFactors (Oxford, England)Review
Corrections and comments
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Authors and funding
16 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.