ArticleThe Journal of clinical investigation2016
Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition.
Article in The Journal of clinical investigation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 688 papers, 3 of them syntheses 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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
688 citing papers in PubMed, 3 syntheses or guidelines pooled 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
- Strategies and mechanisms for the enhancement of chimeric antigen receptor T-cell functions.Science China. Life sciences · 2026Pooled it
- The synergistic immunotherapeutic impact of engineered CAR-T cells with PD-1 blockade in lymphomas and solid tumors: a systematic review.Frontiers in immunology · 2024Pooled it
- CD30 CAR-T cells in combination with anti-PD-1 camrelizumab in relapsed/refractory CD30Journal of translational medicine · 2026Trial
- Axicabtagene Ciloleucel in Combination with Atezolizumab in Patients with Refractory Diffuse Large B-Cell Lymphoma: The Phase 1/2 ZUMA-6 Trial.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- Chimeric antigen receptor T (CAR-T) cell therapy in non-oncological diseases.Signal transduction and targeted therapy · 2026Review
- Bruton's Tyrosine Kinase Inhibitors: Mechanisms, Efficacy, Toxicities and Applications for the Treatment of Human Diseases.MedComm · 2026Review
- Barriers and Blueprints: Next-Generation Engineering Strategies for CAR-T Cell Therapy in Gastrointestinal Tumors.Pharmaceuticals (Basel, Switzerland) · 2026Review
- 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
- A Festschrift Celebrating Dr. Dimiter Stanchev Dimitrov: Antibodies, Innovation, and Impact on Infectious Disease and Cancer Research.Antibodies (Basel, Switzerland) · 2026Article
- Adoptive cell therapy in lung cancer: progress, challenges, and prospects.Chinese medical journal pulmonary and critical care medicine · 2026Review
- Linperlisib enhances MUC1-Tn CAR T cell efficacy by inhibiting EGR1/DUSP2 axis to prevent CAR T cell exhaustion.Leukemia · 2026Article
- From Delivery to Design: Site-Specific Genome Engineering for Next-Generation CAR T-Cell Therapy.Biomedicines · 2026Review
- Article
- Mechanisms, optimization strategies, and salvage options for CAR-T cell therapy.Biomarker research · 2026Review
- IL7-Receptor-Targeted CAR T-Cell Therapy for T-Cell Acute Lymphoblastic Leukemia.Nature communications · 2026Article
- Loss of tumor suppressor NF2 mediates resistance to CAR T cell and anti-PD-1 therapy: Strategies to restore immunotherapy sensitivity.Med (New York, N.Y.) · 2026Article
- Intracranially injected chimeric antigen receptor T cells eradicate glioblastoma cells but have limited potential to persist in the brain in a syngeneic mouse model.Cancer immunology, immunotherapy : CII · 2026Article
- A bibliometric and visualized analysis of CAR-T or TCR-T in solid tumor (from 2015 to 2024).Discover oncology · 2026Article
- Blockade of co-inhibitory receptor immune checkpoint protein TIM3/CD366 augments the anti-cancer activity of CAR-T therapy in solid tumors: An ovarian cancer example.Genes & diseases · 2026Article
628 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies.
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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.