ArticleCancer immunology research2021
Modifications to the Framework Regions Eliminate Chimeric Antigen Receptor Tonic Signaling.
Article in Cancer immunology research, 2021. 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
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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.
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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
55 citing papers in PubMed, 73 citations in OpenAlex.
- Spectrum, pathobiology, mechanistic insights and diagnostic challenges of post-CAR T cell therapy lymphoproliferative disorders.Nature reviews. Clinical oncology · 2026Review
- Engineering CAR-Tregs with Phage-Selected scFv Enables a New Paradigm for Immune Regulation.BioEssays : news and reviews in molecular, cellular and developmental biology · 2026Review
- Humanized and Charge-Optimized CSPG4-Specific CAR-T Cells show Enhanced Efficacy against Head and Neck Squamous Cell Carcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Development of CAR NK Cell Lines Selectively Targeting Cancer Cells Expressing Membrane Hsp70.MedComm · 2026Article
- Membrane-Based Assembly and Interactions in Immune Receptors.Chemical reviews · 2026Review
- Auto-inducible expression of chimeric antigen receptor T cells using the NR4A1 promoter.Immunology and cell biology · 2026Article
- Mechanistic basis and therapeutic modulation of T cell fitness to enhance CAR-T cell efficacy in hematological malignancies.Frontiers in immunology · 2026Review
- Targeting CAR-T cell exhaustion in non-Hodgkin lymphoma: mechanistic insights and emerging clinical strategies.Frontiers in immunology · 2026Review
- Lactic acid improves Treg manufacturing andMolecular therapy. Methods & clinical development · 2025Article
- The Current Landscape of Modular CAR T Cells.International journal of molecular sciences · 2025Review
- A novel mannan-specific chimeric antigen receptor M-CAR redirects T cells to interact withBioengineered · 2025Article
- Article
- De Novo Design of High-Affinity HER2-Targeting Protein Minibinders.Biomolecules · 2025Article
- Targeting CSPG4 enhances the anti-tumor activity of CAR-NK cells for glioblastoma.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Barriers and solutions for CAR-T therapy in solid tumors.Cancer gene therapy · 2025Review
- CAR T-cell immunotherapy as the next horizon in cancer eradication: current landscape, challenges, and future directions.Medical oncology (Northwood, London, England) · 2025Review
- Emerging CAR immunotherapies: broadening therapeutic horizons beyond cancer.Clinical and experimental medicine · 2025Review
- CAR Binders Affect CAR T-cell Tonic Signaling, Durability, and Sensitivity to Target.Cancer immunology research · 2025Article
- Article
- B7-H3 and CSPG4 co-targeting as Pan-CAR-T cell treatment of triple-negative breast cancer.Journal for immunotherapy of cancer · 2025Article
Corrections and comments
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Authors and funding
19 authors at 5 institutions in 3 countries.
Funding
Abstract
Chimeric antigen receptor (CAR) tonic signaling, defined as spontaneous activation and release of proinflammatory cytokines by CAR-T cells, is considered a negative attribute because it leads to impaired antitumor effects. Here, we report that CAR tonic signaling is caused by the intrinsic instability of the mAb single-chain variable fragment (scFv) to promote self-aggregation and signaling via the CD3ζ chain incorporated into the CAR construct. This phenomenon was detected in a CAR encoding either CD28 or 4-1BB costimulatory endodomains. Instability of the scFv was caused by specific amino acids within the framework regions (FWR) that can be identified by computational modeling. Substitutions of the amino acids causing instability, or humanization of the FWRs, corrected tonic signaling of the CAR, without modifying antigen specificity, and enhanced the antitumor effects of CAR-T cells. Overall, we demonstrated that tonic signaling of CAR-T cells is determined by the molecular instability of the scFv and that computational analyses of the scFv can be implemented to correct the scFv instability in CAR-T cells with either CD28 or 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.