ArticleCell reports. Medicine2021
Synergistic T cell signaling by 41BB and CD28 is optimally achieved by membrane proximal positioning within parallel chimeric antigen receptors.
Article in Cell reports. Medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers, 1 of them a synthesis that pooled it.
What it found
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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.
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Who cites it
40 citing papers in PubMed, 1 synthesis or guideline pooled it, 53 citations in OpenAlex.
- 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
- Harnessing the NKG2D immune surveillance pathway using engineered T-cells for the treatment of human disease.Human vaccines & immunotherapeutics · 2026Review
- CAR-T cell therapy: potential for paediatric brain tumours-an update.Journal of neuro-oncology · 2026Review
- DOSET: dose optimization with simultaneous efficacy and toxicity evaluation, motivated by a first-in-human phase I CAR T lymphoma trial.ESMO open · 2026Article
- CRISPR-Cas9 engineering of CAR-T cells: Can non-viral nanoparticles unlock safer and scalable genome editing?iScience · 2026Review
- Optimization of a parallel CAR for B-cell lymphoma via ITAM attenuation and target specificity validation.Clinical and experimental immunology · 2026Article
- Cis- and trans-binding chimeric costimulatory receptors enhance T-cell fitness and tumor control.Cellular & molecular immunology · 2026Article
- A new era in CAR-NK cell therapy: from technological innovations to clinical applications.World journal of pediatrics : WJP · 2026Review
- Next-generation CAR-T cells design: leveraging tumor features for enhanced efficacy.Molecular cancer · 2025Review
- Optimal pairing of binder and co-stimulatory domains improves dual CART cell efficacy.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Article
- Current challenges and emerging opportunities of chimeric antigen receptor-engineered cell immunotherapy.Experimental hematology & oncology · 2025Review
- B7-H3 and CSPG4 co-targeting as Pan-CAR-T cell treatment of triple-negative breast cancer.Journal for immunotherapy of cancer · 2025Article
- NKG2D/CD28 chimeric receptor boosts cytotoxicity and durability of CAR-T cells for solid and hematological tumors.Experimental hematology & oncology · 2025Article
- Diverse potential of chimeric antigen receptor-engineered cell therapy: Beyond cancer.Clinical and translational medicine · 2025Review
- Dissecting the role of CAR signaling architectures on T cell activation and persistence using pooled screens and single-cell sequencing.Science advances · 2025Article
- From molecular design to clinical translation: dual-targeted CAR-T strategies in cancer immunotherapy.International journal of biological sciences · 2025Review
- Advances in CAR optimization strategies based on CD28.Frontiers in immunology · 2025Review
- Senescent immune cells in the tumor microenvironment: emerging insights into cancer immunotherapy resistance.Frontiers in immunology · 2025Review
- Solid tumor immunotherapy using NKG2D-based adaptor CAR T cells.Cell reports. Medicine · 2024Article
- Fueling CARs: metabolic strategies to enhance CAR T-cell therapy.Experimental hematology & oncology · 2024Review
Corrections and comments
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Authors and funding
22 authors at 3 institutions in 1 country.
Funding
Abstract
Second generation (2G) chimeric antigen receptors (CARs) contain a CD28 or 41BB co-stimulatory endodomain and elicit remarkable efficacy in hematological malignancies. Third generation (3G) CARs extend this linear blueprint by fusing both co-stimulatory units in series. However, clinical impact has been muted despite compelling evidence that co-signaling by CD28 and 41BB can powerfully amplify natural immune responses. We postulate that effective dual co-stimulation requires juxta-membrane positioning of endodomain components within separate synthetic receptors. Consequently, we designed parallel (p)CARs in which a 2G (CD28+CD3ζ) CAR is co-expressed with a 41BB-containing chimeric co-stimulatory receptor. We demonstrate that the pCAR platform optimally harnesses synergistic and tumor-dependent co-stimulation to resist T cell exhaustion and senescence, sustaining proliferation, cytokine release, cytokine signaling, and metabolic fitness upon repeated stimulation. When engineered using targeting moieties of diverse composition, affinity, and specificity, pCAR T cells consistently elicit superior anti-tumor activity compared with T cells that express traditional linear CARs.
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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.