ArticleNature medicine2015
4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors.
Article in Nature medicine, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 3 registered trials, which are not on this map. Cited by 1,201 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.
Clinical Study of CAIX-targeted CAR-T Cells in the Treatment of Advanced Renal Cell Carcinoma
A Phase 1 Multicenter, Open Label Trial Evaluating the Safety and Efficacy of DuoCAR20.19.22-D95 in Adult Patients With Relapsed or Refractory B-cell Malignancies
A Multicenter, Open-Label, Non-Randomized, Single-Arm Investigator-Initiated Trial to Evaluate the Safety and Efficacy of IL13Rα2 CAR-T Cells Secreting Anti-PD-L1 Antibody in Patients With Recurrent Malignant Glioma
Who cites it
1,201 citing papers in PubMed, 1,752 citations in OpenAlex.
- Research trends and hotspots of CAR-T cell therapy for acute lymphoblastic leukemia: A bibliometric analysis.Human vaccines & immunotherapeutics · 2026Article
- Fine-tuning affinity and spacer design enhances T cell potency in DLL3 and BCMA CAR T cells.mAbs · 2026Article
- Intelligent immunotherapy: AI-driven optimization of CAR-T therapy in hematologic malignancies.iScience · 2026Review
- CAR-T-centered sequential therapy: current status, challenges, and future clinical perspectives.Journal of hematology & oncology · 2026Review
- Next-generation natural killer cell therapy: bench to bedside and beyond.Signal transduction and targeted therapy · 2026Review
- CRISPRa screen unveils noncanonical NF-κB to boost the antitumor activity of TCR-based CAR-T cells.Cellular & molecular immunology · 2026Article
- Validation and analysis of 12,000 AI-driven CAR-T designs in the Bits to Binders competition.Molecular systems biology · 2026Article
- Targeting CD28 on T lineage malignancies with chimeric antigen receptor T cells.Nature communications · 2026Article
- Multi-dimensional orchestration of binders for improved CAR-T immunotherapy.Cancer letters · 2026Review
- Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.Signal transduction and targeted therapy · 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
- Generation of Allogeneic CAR-T Circumvents Functional Deficits in Patient-Derived Autologous Product for Glioblastoma.International journal of cancer · 2026Article
- Recent advances in molecular mechanisms to improve the efficacy of CAR-T cell therapy for viral diseases, cancer, and autoimmune diseases.Stem cell research & therapy · 2026Review
- T cell senescence and exhaustion: molecular mechanisms and immune rejuvenation for cancer immunotherapy.Signal transduction and targeted therapy · 2026Review
- Adoptive cell therapy in lung cancer: progress, challenges, and prospects.Chinese medical journal pulmonary and critical care medicine · 2026Review
- Cardiotoxicity of T cell immunotherapies.Nature reviews. Cardiology · 2026Review
- Englumafusp alfa plus glofitamab in B cell non-Hodgkin lymphoma: a phase 1 trial.Nature medicine · 2026Article
- Linperlisib enhances MUC1-Tn CAR T cell efficacy by inhibiting EGR1/DUSP2 axis to prevent CAR T cell exhaustion.Leukemia · 2026Article
- Cell-based cancer immunotherapy: milestones, mechanistic insights, and emerging therapeutic directions.Acta pharmacologica Sinica · 2026Review
- A spatially resolved implantable microdevice for multiplexed in situ screening of engineered cellular therapies in solid tumors.Science advances · 2026Article
1,141 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
15 authors at 1 institution in 1 country.
Funding
Abstract
Chimeric antigen receptors (CARs) targeting CD19 have mediated dramatic antitumor responses in hematologic malignancies, but tumor regression has rarely occurred using CARs targeting other antigens. It remains unknown whether the impressive effects of CD19 CARs relate to greater susceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CAR itself. We show that tonic CAR CD3-ζ phosphorylation, triggered by antigen-independent clustering of CAR single-chain variable fragments, can induce early exhaustion of CAR T cells that limits antitumor efficacy. Such activation is present to varying degrees in all CARs studied, except the highly effective CD19 CAR. We further determine that CD28 costimulation augments, whereas 4-1BB costimulation reduces, exhaustion induced by persistent CAR signaling. Our results provide biological explanations for the antitumor effects of CD19 CARs and for the observations that CD19 CAR T cells incorporating the 4-1BB costimulatory domain are more persistent than those incorporating CD28 in clinical trials.
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.