ArticleCancer immunology research2020
Excessive Costimulation Leads to Dysfunction of Adoptively Transferred T Cells.
Article in Cancer immunology research, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 32 citations in OpenAlex.
- Unbiased avidity-based isolation of antigen-specific T cells.Journal for immunotherapy of cancer · 2026Article
- Endogenous CD28 Drives the Persistent Activity of CAR T Cells in Myeloma and Lymphoma Models.Blood cancer discovery · 2026Article
- CD147 regulates CD8iScience · 2026Article
- Targeting urological cancers with CAR-T cell therapy: current landscape and future directions.Journal of translational medicine · 2026Review
- Modular delivery of co-stimulatory signals through a PD-1-based immunoswitch receptor improves the functionality of Hepatitis B Virus-specific engineered T cells.Frontiers in immunology · 2026Article
- Adoptive T Cell therapy for cancer and autoimmune disease: current advances, challenges, and future directions.Oncology reviews · 2026Article
- Reading the immune clock: a machine learning model predicts mouse immune age from cellular patterns.Nature communications · 2025Article
- Challenges and strategies in clinical applications of CAR-T therapy for autoimmune diseases.Journal of hematology & oncology · 2025Review
- The challenges and progress of CAR-T cell therapy in the treatment of solid tumors.Molecular and cellular biochemistry · 2025Review
- CAR-T Cell Manufacturing for Hematological and Solid Tumors: From the Preclinical to Clinical Point of View.Cancer medicine · 2025Review
- CD28 co-stimulation: novel insights and applications in cancer immunotherapy.Nature reviews. Immunology · 2024Review
- CAR T-cells targeting FGFR4 and CD276 simultaneously show potent antitumor effect against childhood rhabdomyosarcoma.Nature communications · 2024Article
- Endogenous CD28 drives CAR T cell responses in multiple myeloma.bioRxiv : the preprint server for biology · 2024Article
- Challenges and strategies associated with CAR-T cell therapy in blood malignancies.Experimental hematology & oncology · 2024Review
- High specificity of engineered T cells with third generation CAR (CD28-4-1BB-CD3-ζ) based on biotin-bound monomeric streptavidin for potential tumor immunotherapy.Frontiers in immunology · 2024Article
- c-Kit signaling potentiates CAR T cell efficacy in solid tumors by CD28- and IL-2-independent co-stimulation.Nature cancer · 2023Article
- IL-18-secreting CAR T cells targeting DLL3 are highly effective in small cell lung cancer models.The Journal of clinical investigation · 2023Article
- Co-Stimulatory Receptor Signaling in CAR-T Cells.Biomolecules · 2022Review
- Emerging Approaches for Solid Tumor Treatment Using CAR-T Cell Therapy.International journal of molecular sciences · 2021Review
- 4-1BB and optimized CD28 co-stimulation enhances function of human mono-specific and bi-specific third-generation CAR T cells.Journal for immunotherapy of cancer · 2021Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Although clinical responses with CD19-targeting chimeric antigen receptor (CAR) T-cell treatment have been observed in patients with certain hematologic malignancies, high rates of disease relapse highlight the necessity to understand and improve mechanisms of CAR T-cell failure. Because T-cell dysfunction is thought to contribute to CAR T-cell treatment failure, understanding what mechanisms drive T cells into this dysfunctional state may aid optimal design of efficacious CAR T cells. Dysfunctional CAR T cells have been characterized as having upregulated inhibitory receptors and decreased cytolytic capabilities. Previous studies have identified a role for sustained CAR CD3ζ signaling in CAR T-cell dysfunction. Here, we demonstrate a mechanism that drives dysfunction in CAR T cells through excessive costimulation. Fully activated CD19-targeted CAR T cells were rendered dysfunctional upon stimulation with both endogenous CD28 stimulation and CAR-mediated CD28 costimulation. Costimulation-driven dysfunction of CAR T cells was demonstrated in a syngeneic immunocompetent mouse model, in which CAR T cells were activated with signals 1 (CD3ζ), 2 (CD28), and 3 (IL12). Thus, we show that CAR T-cell dysfunction can be driven through excessive CD28 and 4-1BB costimulation.
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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.