ArticleBlood2023
Costimulatory domains direct distinct fates of CAR-driven T-cell dysfunction.
Article in Blood, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
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
55 citing papers in PubMed, 49 citations in OpenAlex.
- Histone marks identify novel transcription factors that parse CAR-T subset-of-origin, clinical potential and expansion.Nature communications · 2024Trial
- Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19Nature medicine · 2024Trial
- CAR signaling instructs divergent metabolic reprogramming and functional fates in αβ and γδ T cells.Cellular & molecular immunology · 2026Article
- Tisa-cel and axi-cel CAR structure influences the development of resistance to CD19-CAR-T therapy.Leukemia · 2026Article
- αvβ3 CAR-T Cells Simultaneously Targeting Tumor and Metastases Produce Highly Effective Control in Preclinical Models of Melanoma and Triple-Negative Breast Cancer.Molecular cancer therapeutics · 2026Article
- Fate induction through asymmetric T cell division is modulated by chimeric antigen receptor costimulatory domains.Nature immunology · 2026Article
- Cell-autonomous control of CAR signaling and receptor shedding via ADAM17-mediated proteolysis.Cell · 2026Article
- Review
- Balancing the efficacy and safety of chimeric antigen receptor T-cell therapy by affinity combination.Nature communications · 2026Article
- Dynamic regulation of BACH2 enhances CAR T cell function.Molecular therapy. Oncology · 2026Article
- CD4-Based Chimeric Antigen Receptor (CAR)-T Cells With Resistance to HIV-1 Infection and Enhanced Anti-HIV Efficacy: Covalent Interaction Between CD4-CAR and HIV-1 Envelope Glycoprotein.Journal of medical virology · 2026Article
- BACH2 regulates T cell lineage state to enhance CAR T cell function.Nature immunology · 2026Article
- The race between 4-1BB- and CD28-based CD19 CAR-T products in the therapy of B-cell malignancies.Biochimica et biophysica acta. Reviews on cancer · 2026Review
- CAR-adapted PIK3CD base editing enhances T cell anti-tumor potency.Nature cancer · 2026Article
- Optimally engineered HLA/peptide-specific CAR-T cells outperform TCR-T cells to eradicate solid tumors.Science advances · 2026Article
- CAR Intrinsic Design Pre-Shapes Transcriptional and Metabolic Networks in CAR T Cells.Metabolites · 2026Article
- Chemokines as regulators of CAR-T cell trafficking, function, and context-dependent tumor cell death.Frontiers in immunology · 2026Review
- Rewriting CAR-T cell fate: CRISPR/Cas gene editing for solid tumor therapy.Frontiers in immunology · 2026Review
- Reprogramming CAR T cells across genetic, epigenetic, metabolic and microenvironmental axes to improve efficacy and safety in cancer and autoimmune disease.Frontiers in immunology · 2026Review
- Advances in Biomarkers for CAR-T Treatment Resistance in Diffuse Large B-Cell Lymphoma.Mini reviews in medicinal chemistry · 2026Review
Corrections and comments
- Commented on by
- Update of
Authors and funding
21 authors at 2 institutions in 1 country.
Funding
Abstract
T cells engineered to express chimeric antigen receptors (CARs) targeting CD19 have demonstrated impressive activity against relapsed or refractory B-cell cancers yet fail to induce durable remissions for nearly half of all patients treated. Enhancing the efficacy of this therapy requires detailed understanding of the molecular circuitry that restrains CAR-driven antitumor T-cell function. We developed and validated an in vitro model that drives T-cell dysfunction through chronic CAR activation and interrogated how CAR costimulatory domains, central components of CAR structure and function, contribute to T-cell failure. We found that chronic activation of CD28-based CARs results in activation of classical T-cell exhaustion programs and development of dysfunctional cells that bear the hallmarks of exhaustion. In contrast, 41BB-based CARs activate a divergent molecular program and direct differentiation of T cells into a novel cell state. Interrogation using CAR T cells from a patient with progressive lymphoma confirmed the activation of this novel program in a failing clinical product. Furthermore, we demonstrate that 41BB-dependent activation of the transcription factor FOXO3 is directly responsible for impairing CAR T-cell function. These findings identify that costimulatory domains are critical regulators of CAR-driven T-cell failure and that targeted interventions are required to overcome costimulation-dependent dysfunctional programs.
Indexed as
Identifiers
What OpenQuestion holds
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.