ArticleClinical cancer research : an official journal of the American Association for Cancer Research2024
Mesothelin CAR T Cells Secreting Anti-FAP/Anti-CD3 Molecules Efficiently Target Pancreatic Adenocarcinoma and its Stroma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 86 papers.
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86 citing papers in PubMed, 91 citations in OpenAlex.
- Review
- Comparative clinical outcomes and single-cell profiling of CD19 CAR-T versus blinatumomab for relapsed/refractory B-ALL.Journal for immunotherapy of cancer · 2026Article
- Biomarker-Driven Strategies for Stromal Reprogramming in Pancreatic Ductal Adenocarcinoma.Cells · 2026Review
- Immunotherapy for Digestive System Cancers: Progress, Challenges, and Future Directions.Biomedicines · 2026Review
- The Evolution of FAP-Targeted CAR T-Cell Therapy in Solid Tumors: From Immunotherapy to Immunotheranostic Applications.International journal of molecular sciences · 2026Review
- Advances, challenges, and innovative strategies of CAR-T cell therapy in pancreatic cancer.Biomarker research · 2026Review
- Unraveling the roles of fibroblast activation protein‑positive cancer‑associated fibroblasts in cancer: From mechanisms to therapy (Review).International journal of oncology · 2026Review
- Mechanobiology of CAR-T cell therapy: regulatory mechanisms and strategies for enhanced antitumor immunity.Journal of translational medicine · 2026Review
- Pathophysiology of colitis-associated colorectal cancer.Nature reviews. Gastroenterology & hepatology · 2026Review
- Mechanobiology of the tumor microenvironment: a review of therapeutic interactions and in vitro elasticity measurement techniques.Journal of biomedical science · 2026Review
- Optimizing CAR T cell therapy in pancreatic cancer through clinically actionable combinations.Molecular therapy. Oncology · 2026Article
- Deconstructing cancer in 3D: models, mechanisms, and personalized solutions.Molecular cancer · 2026Review
- Nanomaterials targeting cancer-associated fibroblasts to overcome stromal barriers in cancer immunotherapy.Journal of nanobiotechnology · 2026Review
- Review
- Design, Synthesis, and Evaluation of OncoFAP Derivatives with the Albumin Binder as Novel Antitumor Radiopharmaceuticals.Chemical & biomedical imaging · 2026Article
- Integrative multimodal transcriptomics identifies a cancer-associated fibroblast membrane signature for predicting prognosis and therapeutic response in pancreatic ductal adenocarcinoma.Journal of molecular medicine (Berlin, Germany) · 2026Article
- MSCs delivering LIGHT prime immune response against CAFs to harness antigen loss variants.Cancer gene therapy · 2026Article
- Clinical value of clinicopathological, ultrasonographic features and fibroblast activation protein in evaluating the radioiodine treatment efficacy in papillary thyroid carcinoma.Annals of nuclear medicine · 2026Article
- Heterocellular crosstalk and architecture of the pancreatic tumour microenvironment.Nature reviews. Cancer · 2026Review
- Organoids: technology refining, current applications and future directions.Molecular biomedicine · 2026Review
26 more citing papers are in PubMed but not listed here.
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Authors and funding
39 authors at 3 institutions in 1 country.
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Abstract
purposeTargeting solid tumors with chimeric antigen receptor (CAR) T cells remains challenging due to heterogenous target antigen expression, antigen escape, and the immunosuppressive tumor microenvironment (TME). Pancreatic cancer is characterized by a thick stroma generated by cancer-associated fibroblasts (CAF), which may contribute to the limited efficacy of mesothelin-directed CAR T cells in early-phase clinical trials. To provide a more favorable TME for CAR T cells to target pancreatic ductal adenocarcinoma (PDAC), we generated T cells with an antimesothelin CAR and a secreted T-cell-engaging molecule (TEAM) that targets CAF through fibroblast activation protein (FAP) and engages T cells through CD3 (termed mesoFAP CAR-TEAM cells). EXPERIMENTAL
designUsing a suite of in vitro, in vivo, and ex vivo patient-derived models containing cancer cells and CAF, we examined the ability of mesoFAP CAR-TEAM cells to target PDAC cells and CAF within the TME. We developed and used patient-derived ex vivo models, including patient-derived organoids with patient-matched CAF and patient-derived organotypic tumor spheroids.
resultsWe demonstrated specific and significant binding of the TEAM to its respective antigens (CD3 and FAP) when released from mesothelin-targeting CAR T cells, leading to T-cell activation and cytotoxicity of the target cell. MesoFAP CAR-TEAM cells were superior in eliminating PDAC and CAF compared with T cells engineered to target either antigen alone in our ex vivo patient-derived models and in mouse models of PDAC with primary or metastatic liver tumors.
conclusionsCAR-TEAM cells enable modification of tumor stroma, leading to increased elimination of PDAC tumors. This approach represents a promising treatment option for pancreatic cancer.
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