ArticleJournal for immunotherapy of cancer2026
Membrane-bound TRAIL-armoring augments CAR-T cells in mesothelin-positive solid malignancies.
Article in Journal for immunotherapy of cancer, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundMesothelin (MSLN)-targeted chimeric antigen receptor (CAR)-T cell therapy shows an effective and long-lasting response in high MSLN-expressing tumors, but fails to treat tumors with heterogeneous levels of antigen expression. Here we describe an innovative approach where a stable tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) chimera, referred to as membrane-bound (MB)-TRAIL, is expressed on the cell surface of MSLN-specific (M28z) CAR-T cells. This potentiates their overall anticancer activity by overcoming heterogeneous antigen expression in tumor lesions.
methodsWe engineered MB-TRAIL-armored MSLN-directed M28z CAR-T cells and assessed their in vitro toxicity using flow cytometry against tumor target cells with heterogeneous MSLN expression. Triple-multiplex bioluminescence imaging using three different reporter genes enabled simultaneous in vivo non-invasive and longitudinal assessment of CAR-T cell dynamics, as well as MSLN+ and MSLN- tumor responses in xenograft models of MSTO-211H pleural mesothelioma (PM) and A549 non-small cell-lung cancer (NSCLC) with heterogeneous antigen expression. We further tested the therapeutic benefit of combining MB-TRAIL-armored CAR-T cells with the clinically used TRAIL sensitizer, doxorubicin, in an A549 xenograft model.
resultsMB-TRAIL M28z CAR-T cell therapy provides pro-apoptotic stimuli to both MSLN+ and MSLN- tumors, significantly improving survival in models of MSTO-211H PM and A549 NSCLC with heterogeneous antigen expression. We also demonstrated that our treatment confers sustained protection against metastatic spread in the MSTO-211H model, whereas doxorubicin overcomes TRAIL resistance rendering the A549 model more susceptible to MB-TRAIL M28z CAR-T cell therapy and reducing metastatic growth.
conclusionsOur strategy confers superior antitumor efficacy relative to clinically trialed M28z CAR-T cells by directly targeting heterogeneous tumor antigen expression. These results constitute the foundation for developing a new class of clinically translatable TRAIL-armored CAR-T cell immunotherapies for the treatment of a wider range of malignancies.
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