ArticleJCI insight2024
Affinity-tuned mesothelin CAR T cells demonstrate enhanced targeting specificity and reduced off-tumor toxicity.
Article in JCI insight, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed.
- JNJ-79032421, a Novel Membrane-Restricted Mesothelin-Targeting T Cell-Engaging Bispecific Antibody for the Treatment of Mesothelin-Positive Cancers.Molecular cancer therapeutics · 2026Article
- Review
- Multi-dimensional orchestration of binders for improved CAR-T immunotherapy.Cancer letters · 2026Review
- Recognition of ErbB Family Dimers by the EGF-like Domain of NRG1alpha and Beta: Implications for Ligand-Based CAR Therapy.International journal of molecular sciences · 2026Article
- αvβ3 CAR-T Cells Simultaneously Targeting Tumor and Metastases Produce Highly Effective Control in Preclinical Models of Melanoma and Triple-Negative Breast Cancer.Molecular cancer therapeutics · 2026Article
- Review
- Synergistic Antitumor Efficacy of Radiofrequency Ablation Combined With TROP2-CAR-T Cells in a Xenograft Mouse Model of Lung Adenocarcinoma.Thoracic cancer · 2026Article
- Portal Fibroblasts: A Hidden Driver of Cholestasis-Associated Liver Cancer.Cellular and molecular gastroenterology and hepatology · 2026Article
- Affinity and costimulatory architecture-associated toxicity in mesothelin-targeted TCR-mimetic CAR-T cells.Frontiers in immunology · 2026Article
- Next-generation immune cell therapies for lung cancer: advances in CAR-T, NK, and TIL strategies.Frontiers in medicine · 2026Review
- Mesothelin/Mucin 16 Signaling in Activated Portal Fibroblasts Drives the Development of Cholestatic Fibrosis and Hepatocellular Carcinoma in Aged Female Multidrug Resistance Protein 2 Knockout Mice.Cellular and molecular gastroenterology and hepatology · 2026Article
- Engineering a juxtamembrane-targeting CAR T-cell against mesothelin: a novel binder resilient to shed antigen for enhanced efficacy against ovarian and pancreatic cancer.Frontiers in immunology · 2026Article
- The Current Landscape of Modular CAR T Cells.International journal of molecular sciences · 2025Review
- Chimeric antigen receptor T cell therapy: Revolutionizing cancer treatment.World journal of clinical oncology · 2025Review
- The Tumor Environment in Peritoneal Carcinomatosis and Malignant Pleural Effusions: Implications for Therapy.Cancers · 2025Review
- Constructing the cure: engineering the next wave of antibody and cellular immune therapies.Journal for immunotherapy of cancer · 2025Review
- Nanobodies and their derivatives: pioneering the future of cancer immunotherapy.Cell communication and signaling : CCS · 2025Review
- Advancing biliary tract malignancy treatment: emerging frontiers in cell-based therapies.Frontiers in immunology · 2025Review
Corrections and comments
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Authors and funding
9 authors.
Funding
Abstract
The application of chimeric antigen receptor (CAR) T cell therapy in solid tumors is hindered by life-threatening toxicities resulting from on-target, off-tumor killing of nonmalignant cells that express low levels of the target antigen. Mesothelin (MSLN) has been identified as a target antigen for CAR T cell treatment of mesothelioma, lung, ovarian, and other cancers because of its high expression on tumor cells and limited expression on mesothelial cells. However, fatal off-tumor toxicity of high-affinity MSLN-targeting CAR T cells has been reported in multiple clinical trials. In this study, we constructed CARs using mutant variants of a single-domain nanobody that bind both human and mouse MSLN with a wide range of affinities and examined tumor responses and their toxicities from on-target, off-tumor interactions in mouse models. CAR T cells with low nanomolar affinity (equilibrium dissociation constant, KD) exhibited profound systemic expansion with no apparent infiltration into the tumor. With a gradual reduction of CAR affinity toward the micromolar KD, the expansion of CAR T cells became more restricted to tumors. Our preclinical studies demonstrated that high-affinity MSLN CARs were associated with fatal on-target, off-tumor toxicity and that affinity-tuned CARs rendered T cells more selective for MSLN-high tumors.
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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.