ArticleScience translational medicine2021
Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity.
Article in Science translational medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 238 papers, 2 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
238 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Hyperprogressive disease in carcinoma induced by immune checkpoint inhibitor therapy: a systematic review.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Pooled it
- Mapping the clinical landscape of multifunctional CAR T cells: Targets, trends, and synergies.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Pooled it
- Demethylation-primed tandem CD19/CD20 CAR T cells in relapsed/refractory B-cell lymphoma: a phase I/II trial.Nature communications · 2026Trial
- CRISPR in clinical oncology: translational advances from molecular diagnostics to therapeutics.Nature reviews. Clinical oncology · 2026Review
- Clonal Hematopoiesis and CAR T Cell Therapy: From Biological Crosstalk to Clinical Implications.International journal of laboratory hematology · 2026Review
- Overcoming T cell exhaustion and senescence in CAR T cell therapy for solid tumors.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- Review
- Targeting Regnase-1 in B7-H3-CAR T cells reprograms the tumor microenvironment and enhances antitumor efficacy for osteosarcoma.Cell reports. Medicine · 2026Article
- Co-delivery of lentiviral vectors and Cas9-containing virus-like particles enables rapid, scalable manufacture of gene-edited CAR T cells.Molecular therapy. Advances · 2026Article
- PRMT7 restricts CD8+ T cells expansion via the NF-ΚB pathway.Nature communications · 2026Article
- Chimeric antigen receptor (CAR)-T cell therapy for solid tumors in pediatric patients: current breakthroughs, dilemmas, and strategies.Experimental hematology & oncology · 2026Review
- T cell senescence and exhaustion: molecular mechanisms and immune rejuvenation for cancer immunotherapy.Signal transduction and targeted therapy · 2026Review
- Integrated epigenetic and genetic programming of primary human T cells.Nature biotechnology · 2026Article
- Epigenetic insights and innovations for overcoming barriers in CAR-T cell therapy for cancer.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026Review
- DNA Hypomethylating Agents Preserve T-cell Stemness and Potentiate the Efficacy of CD3-Bispecific Antibodies.Cancer immunology research · 2026Article
- Decoding T cell exhaustion in the tumour microenvironment.Experimental & molecular medicine · 2026Review
- ATF7ip Inhibits the Tumor Immune Response by Promoting Terminal CD8+ T-cell Exhaustion.Cancer immunology research · 2026Article
- Spectrum, pathobiology, mechanistic insights and diagnostic challenges of post-CAR T cell therapy lymphoproliferative disorders.Nature reviews. Clinical oncology · 2026Review
- Azacytidine restores T cell function in AML by modulating DNA methylation.bioRxiv : the preprint server for biology · 2026Article
- T Cell Exhaustion in Cancer Immunotherapy: Heterogeneity, Mechanisms, and Therapeutic Opportunities.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
178 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
27 authors.
Funding
Abstract
Chimeric antigen receptor (CAR) T cell therapy is revolutionizing cancer immunotherapy for patients with B cell malignancies and is now being developed for solid tumors and chronic viral infections. Although clinical trials have demonstrated the curative potential of CAR T cell therapy, a substantial and well-established limitation is the heightened contraction and transient persistence of CAR T cells during prolonged antigen exposure. The underlying mechanism(s) for this dysfunctional state, often termed CAR T cell exhaustion, remains poorly defined. Here, we report that exhaustion of human CAR T cells occurs through an epigenetic repression of the T cell’s multipotent developmental potential. Deletion of the de novo DNA methyltransferase 3 alpha (DNMT3A) in T cells expressing first- or second-generation CARs universally preserved the cells’ ability to proliferate and mount an antitumor response during prolonged tumor exposure. The increased functionality of the exhaustion-resistant DNMT3A knockout CAR T cells was coupled to an up-regulation of interleukin-10, and genome-wide DNA methylation profiling defined an atlas of genes targeted for epigenetic silencing. This atlas provides a molecular definition of CAR T cell exhaustion, which includes many transcriptional regulators that limit the “stemness” of immune cells, including CD28, CCR7, TCF7, and LEF1. Last, we demonstrate that this epigenetically regulated multipotency program is firmly coupled to the clinical outcome of prior CAR T cell therapies. These data document the critical role epigenetic mechanisms play in limiting the fate potential of human T cells and provide a road map for leveraging this information for improving CAR T cell efficacy.
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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.