ArticleJournal for immunotherapy of cancer2025
Tandem CAR-T cells targeting mesothelin and MUC16 overcome tumor heterogeneity by targeting one antigen at a time.
Article in Journal for immunotherapy of cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Multi-dimensional orchestration of binders for improved CAR-T immunotherapy.Cancer letters · 2026Review
- Review
- IL-15 boosts mesothelin- and CD70-CAR NK cell potency in PDAC without added benefit from dual targeting.Molecular therapy. Oncology · 2026Article
- Barriers and Blueprints: Next-Generation Engineering Strategies for CAR-T Cell Therapy in Gastrointestinal Tumors.Pharmaceuticals (Basel, Switzerland) · 2026Review
- The evolving landscape of CAR T cell therapy in children and young adults with B cell acute lymphoblastic leukemia.Molecular therapy. Oncology · 2026Review
- Review
- Enhanced PD-L1 targeting boosts the cytotoxic activity of FOLR1- CAR NK92 cells against ovarian cancer.Cancer immunology, immunotherapy : CII · 2026Article
- Distinct O-Linked Glycosylation Systems in Signaling and Immune Regulation.International journal of molecular sciences · 2026Review
- Advances in adoptive cell therapy for ovarian cancer.Frontiers in immunology · 2026Review
- Evaluating mesothelin as an immunotherapeutic target for endogenous T cells.Frontiers in immunology · 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
- CAR-T cell therapy for pancreatic cancer: Translating emerging targets and dual-targeting strategies from solid tumors.Frontiers in immunology · 2026Review
- Emerging Targeted and Multimodal Therapeutic Strategies in Breast Cancer: A Comprehensive Review.Breast cancer (Dove Medical Press) · 2026Review
- Review
- Multiplex engineering and multifunction T cells for precise and effective immunotherapies.Frontiers in immunology · 2025Review
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Authors and funding
18 authors.
Funding
Abstract
backgroundTumor heterogeneity and antigen escape are mechanisms of resistance to chimeric antigen receptor (CAR)-T cell therapy, especially in solid tumors. Targeting multiple antigens with a unique CAR construct could be a strategy for a better tumor control than monospecific CAR-T cells on heterogeneous models. To overcome tumor heterogeneity, we targeted mesothelin (meso) and Mucin 16 (MUC16), two antigens commonly expressed in solid tumors, using a tandem CAR design.
methodsWe designed a series of tandem CAR constructs based on various anti-meso (SS1) and anti-MUC16 ectodomain (MUC16ecto) (4H11) single-chain variable fragment (scFv) arrangements and G4S linker lengths. Then we determined the best tandem CAR design based on binding of soluble antigens, steric hindrance, avidity and functionality against cell lines expressing one or both antigens in vitro. Finally, we compared the tandem CAR to monospecific CAR-T cells in mixed tumor models in vitro (two-dimensional and three-dimensional models) and in vivo.
resultsWe show that the scFv arrangement and linker length impacted antigen binding and CAR expression in T cells. Tandem CAR configuration (TanCAR1) (with SS1 scFv located distally and one G4S repeat as the linker between scFvs) had the best binding and activation profile in vitro and outperformed SS1 and 4H11 monospecific CAR-T cells in mixed tumor models in vitro and in vivo, showing an antigen-driven killing of tumor cells based on antigen density. Moreover, acoustic force microscopy, using tumor cells with different levels of antigen expression, revealed that TanCAR1-T cells likely bind to one antigen at a time rather than simultaneously.
conclusionsThis is the first time using a tandem CAR design targeting meso and MUC16, and demonstrating a benefit on tumor control over monospecific CAR-T cells. Tandem CAR-T cells targeting meso and MUC16ecto could be employed as a strategy to overcome tumor cell heterogeneity in ovarian and pancreatic tumors, and may help to design therapeutic approaches relying on its one-antigen-at-a-time binding properties and on its antigen-driven killing of tumor cells based on antigen density.
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