ArticleMolecular cancer2025
Differential susceptibility and role for senescence in CART cells based on costimulatory domains.
Article in Molecular cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
8 citing papers in PubMed.
- T cell senescence and exhaustion: molecular mechanisms and immune rejuvenation for cancer immunotherapy.Signal transduction and targeted therapy · 2026Review
- TRAIL splice variant TRAILshort disrupts T cell receptor signaling and promotes immune tolerance in vivo.The Journal of clinical investigation · 2026Article
- Mechanisms, optimization strategies, and salvage options for CAR-T cell therapy.Biomarker research · 2026Review
- SIRT2-mediated deacetylation of LCK governs the magnitude of T cell receptor signaling.Nature immunology · 2026Article
- T-cell senescence and immunosenescence in chronic oral mucosal inflammatory diseases: mechanisms and therapeutic implications.Journal of oral microbiology · 2026Review
- Decoding the tumor-aging axis: from bench to clinical.Frontiers in immunology · 2026Review
- Research advances and application prospects of CAR-T therapy in the treatment of age-related diseases.Frontiers in immunology · 2026Review
- Above and beyond senescence and CAR T cell: advances and future perspectives.Frontiers in immunology · 2025Review
Corrections and comments
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Authors and funding
22 authors.
Funding
Abstract
Despite the success of chimeric antigen receptor T (CART) cell therapy in hematological malignancies, durable remissions remain low. Here, we report CART senescence as a potential resistance mechanism in 41BB-costimulated CART cell therapy. To mimic cancer relapse, we utilized an in vitro model with repeated CART cell activation cycles followed by rest periods. Using CD19-targeted CART cells with costimulation via 4-1BB-CD3ζ (BBζ) or CD28-CD3ζ (28ζ), we showed that CART cells undergo functional, phenotypical, and transcriptomic changes of senescence, which is more prominent in BBζ. We then utilized two additional independent strategies to induce senescence through MYC activation and irradiation. Induction of senescence impaired BBζ activity but improved 28ζ activity in preclinical studies. These findings were supported by analyses of independent patient data sets; senescence signatures in CART cell products were associated with non-response to BBζ but with improved clinical outcomes in 28ζ treatment. In summary, our study identifies senescence as a potential mechanism of failure predominantly in 41BB-costimulated CART 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.