ArticleThe Journal of clinical investigation2021
BET bromodomain protein inhibition reverses chimeric antigen receptor extinction and reinvigorates exhausted T cells in chronic lymphocytic leukemia.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers, 1 of them a synthesis that pooled it.
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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
61 citing papers in PubMed, 1 synthesis or guideline pooled it, 88 citations in OpenAlex.
- Strategies and mechanisms for the enhancement of chimeric antigen receptor T-cell functions.Science China. Life sciences · 2026Pooled it
- Rapamycin-resistant polyclonal Th1/Tc1 cell therapy (RAPA-201) safely induces disease remissions in relapsed, refractory multiple myeloma.Journal for immunotherapy of cancer · 2025Trial
- Review
- Epigenetic reprogramming of T cell metabolism restores function and enhances anti-tumor immunity in lung cancer.Nature immunology · 2026Article
- Epigenetic modifications in cancer drug resistance: molecular mechanisms and therapeutic interventions.Molecular biomedicine · 2026Review
- Fine-tuning BACH2 dosage balances stemness and effector function to enhance antitumor T cell therapy.Nature immunology · 2026Article
- Research progress on resistance mechanisms to CAR-T cell therapy in diffuse large B-cell lymphoma.Frontiers in oncology · 2026Review
- Targeting CAR-T cell exhaustion in non-Hodgkin lymphoma: mechanistic insights and emerging clinical strategies.Frontiers in immunology · 2026Review
- Harnessing the potential of gene editing technology for CAR-T cell therapy of solid tumors.Inflammation and regeneration · 2025Review
- CAR T cell persistence in cancer.Trends in cancer · 2025Review
- Advances in T-Cell-Directed Immunotherapy for Adult Mature B-Cell Lymphoma: A Comprehensive Review of CAR T-Cell and Bispecific Antibody Therapies.Cancer research and treatment · 2025Review
- Differential susceptibility and role for senescence in CART cells based on costimulatory domains.Molecular cancer · 2025Article
- Evolving CAR T-Cell Therapy to Overcome the Barriers in Treating Pediatric Central Nervous System Tumors.Cancer discovery · 2025Review
- Tailoring CAR surface density and dynamics to improve CAR-T cell therapy.Journal for immunotherapy of cancer · 2025Review
- The Elevation and Impact of Peripheral Bile Acids in Chronic Lymphocytic Leukemia.Biomedicines · 2025Article
- Chimeric Antigen Receptor-T Cells in the Modern Era of Chronic Lymphocytic Leukemia Treatment.Cancers · 2025Review
- TET2 gene mutation status associated with poor prognosis of transition zone prostate cancer: a retrospective cohort study based on whole exome sequencing and machine learning models.Frontiers in endocrinology · 2025Article
- A novel mitochondrial pyruvate carrier inhibitor drives stem cell-like memory CAR T cell generation and enhances antitumor efficacy.Molecular therapy. Oncology · 2024Article
- Relapsed/refractory CLL: the role of allo-SCT, CAR-T, and T-cell engagers.Hematology. American Society of Hematology. Education Program · 2024Review
- Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay.Cell reports. Medicine · 2024Article
1 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
33 authors at 6 institutions in 2 countries.
Funding
Abstract
Chimeric antigen receptor (CAR) T cells have induced remarkable antitumor responses in B cell malignancies. Some patients do not respond because of T cell deficiencies that hamper the expansion, persistence, and effector function of these cells. We used longitudinal immune profiling to identify phenotypic and pharmacodynamic changes in CD19-directed CAR T cells in patients with chronic lymphocytic leukemia (CLL). CAR expression maintenance was also investigated because this can affect response durability. CAR T cell failure was accompanied by preexisting T cell-intrinsic defects or dysfunction acquired after infusion. In a small subset of patients, CAR silencing was observed coincident with leukemia relapse. Using a small molecule inhibitor, we demonstrated that the bromodomain and extra-terminal (BET) family of chromatin adapters plays a role in downregulating CAR expression. BET protein blockade also ameliorated CAR T cell exhaustion as manifested by inhibitory receptor reduction, enhanced metabolic fitness, increased proliferative capacity, and enriched transcriptomic signatures of T cell reinvigoration. BET inhibition decreased levels of the TET2 methylcytosine dioxygenase, and forced expression of the TET2 catalytic domain eliminated the potency-enhancing effects of BET protein targeting in CAR T cells, providing a mechanism linking BET proteins and T cell dysfunction. Thus, modulating BET epigenetic readers may improve the efficacy of cell-based immunotherapies.
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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.