ArticleProceedings of the National Academy of Sciences of the United States of America2024
Tumor resistance to anti-mesothelin CAR-T cells caused by binding to shed mesothelin is overcome by targeting a juxtamembrane epitope.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 23 citations in OpenAlex.
- JNJ-79032421, a Novel Membrane-Restricted Mesothelin-Targeting T Cell-Engaging Bispecific Antibody for the Treatment of Mesothelin-Positive Cancers.Molecular cancer therapeutics · 2026Article
- Multi-dimensional orchestration of binders for improved CAR-T immunotherapy.Cancer letters · 2026Review
- Barriers and Blueprints: Next-Generation Engineering Strategies for CAR-T Cell Therapy in Gastrointestinal Tumors.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Advances, challenges, and innovative strategies of CAR-T cell therapy in pancreatic cancer.Biomarker research · 2026Review
- Comparative theranostic efficacy ofEuropean journal of nuclear medicine and molecular imaging · 2026Article
- Emerging Immunotherapy and Antibody-Derived Therapeutics for the Treatment of Advanced Non-Small-Cell Lung Cancer: A Review.Cancers · 2026Review
- Rapid CAR screening and circRNA-driven CAR-NK cells for persistent shed-resistant immunotherapy.Signal transduction and targeted therapy · 2026Article
- Mesothelin biology and the evolving landscape of targeted immunotherapy.Molecular therapy. Oncology · 2026Review
- A monoclonal antibody W1 blocks mesothelin-mediated tumor progression.Molecular therapy. Oncology · 2026Article
- RO4, a high-affinity humanized antibody against the juxtamembrane region of mesothelin for targeted cancer therapy.Antibody therapeutics · 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
- Novel perspectives on MSLN-targeted cancer therapy: from molecular mechanisms to clinical translation.Cancer biology & therapy · 2025Review
- Decoding the role of mesothelin in tumor dynamics and targeted treatment innovations.Molecular biomedicine · 2025Review
- Targeting orthotopic and metastatic pancreatic cancer with allogeneic stem cell-engineered mesothelin-redirected CAR-NKT cells.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Development of a Mesothelin-Binding Engineered Scaffold Protein as a Theranostic for Pleural Mesothelioma.Bioconjugate chemistry · 2025Article
- Advances in ligand-based surface engineering strategies for fine-tuning T cell mechanotransduction toward efficient immunotherapy.Biophysical journal · 2025Review
- Computational modeling and experimental validation of the interaction between tumor biomarker mesothelin and an engineered targeting protein with therapeutic activity.Protein science : a publication of the Protein Society · 2025Article
- Emerging Strategies for Targeting Angiogenesis and the Tumor Microenvironment in Gastrointestinal Malignancies: A Comprehensive Review.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Immuno-oncology recapitulates ontogeny: Modern cell and gene therapy for cancer.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Review
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
Despite many clinical trials, CAR-T cells are not yet approved for human solid tumor therapy. One popular target is mesothelin (MSLN) which is highly expressed on the surface of about 30% of cancers including mesothelioma and cancers of the ovary, pancreas, and lung. MSLN is shed by proteases that cleave near the C terminus, leaving a short peptide attached to the cell. Most anti-MSLN antibodies bind to shed MSLN, which can prevent their binding to target cells. To overcome this limitation, we developed an antibody (15B6) that binds next to the membrane at the protease-sensitive region, does not bind to shed MSLN, and makes CAR-T cells that have much higher anti-tumor activity than a CAR-T that binds to shed MSLN. We have now humanized the Fv (h15B6), so the CAR-T can be used to treat patients and show that h15B6 CAR-T produces complete regressions in a hard-to-treat pancreatic cancer patient derived xenograft model, whereas CAR-T targeting a shed epitope (SS1) have no anti-tumor activity. In these pancreatic cancers, the h15B6 CAR-T replicates and replaces the cancer cells, whereas there are no CAR-T cells in the tumors receiving SS1 CAR-T. To determine the mechanism accounting for high activity, we used an OVCAR-8 intraperitoneal model to show that poorly active SS1-CAR-T cells are bound to shed MSLN, whereas highly active h15B6 CAR-T do not contain bound MSLN enabling them to bind to and kill cancer cells.
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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.