ArticleJournal for immunotherapy of cancer2024
Integrating binding affinity and tonic signaling enables a rational CAR design for augmented T cell function.
Article in Journal for immunotherapy of cancer, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Preclinical advances and mechanistic insights of CAR-T therapy for acute myeloid leukemia: from target iteration to microenvironment regulation.Annals of medicine · 2026Review
- Drug-controlled CAR T cells through the regulation of cell-cell interactions.Nature chemical biology · 2026Article
- Next-generation CAR-T cell therapy against cancer: precision engineering, programmable immunity, and emerging clinical frontiers.Journal of the Egyptian National Cancer Institute · 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
- Review
- Review
- Balancing the efficacy and safety of chimeric antigen receptor T-cell therapy by affinity combination.Nature communications · 2026Article
- Decoding signaling architectures: CAR versus TCR dynamics in solid tumor immunotherapy.Acta biochimica et biophysica Sinica · 2026Review
- AI-guided CAR designs and targeted pathway modulation to enhance multi-antigen CAR T cell durability and overcome antigen escape.Nature communications · 2026Article
- CAR-T cells in solid tumors: engineering, biomarkers, translational pathways and the road ahead.Frontiers in immunology · 2026Review
- CAR T cell cancer immunotherapy: who does the job?Frontiers in immunology · 2026Review
- Mechanistic basis and therapeutic modulation of T cell fitness to enhance CAR-T cell efficacy in hematological malignancies.Frontiers in immunology · 2026Review
- The Current Landscape of Modular CAR T Cells.International journal of molecular sciences · 2025Review
- Challenges and strategies in clinical applications of CAR-T therapy for autoimmune diseases.Journal of hematology & oncology · 2025Review
- From Bench to Bedside: Emerging Paradigms in CAR-T Cell Therapy for Solid Malignancies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- A Tonic Signaling Code Predicts CAR-T Cell Efficacy in Diffuse Midline Glioma.bioRxiv : the preprint server for biology · 2025Article
- CAR T-cell immunotherapy as the next horizon in cancer eradication: current landscape, challenges, and future directions.Medical oncology (Northwood, London, England) · 2025Review
- CAR T-cells meet autoimmune neurological diseases: a new dawn for therapy.Frontiers in immunology · 2025Review
Corrections and comments
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Authors and funding
17 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe success of chimeric antigen receptor (CAR) T cell therapy for hematological malignancies has not yet translated into long-term elimination of solid tumors indicating the need for adequately tuning CAR T cell functionality.
methodsWe leveraged a translational pipeline including biophysical characterization and structural prediction of the CAR binding moiety, evaluation of cellular avidity, synapse formation, T cell motility, and functional capacities under repetitive target challenge and in sustained tumor control.
resultsAs an example of clinical relevance, we derived a panel of anti-Her2 CARs covering a 4-log affinity range, all expected to target the same Her2 epitope. The same scFv mutations increased both antigen-specific affinity, cellular avidity, and antigen-independent "tonic" signaling; above a minimum threshold, raise in affinity translated into functional avidity in a non-linear fashion. In this case, replacement by amino acids of higher hydrophobicity within the scFv coincidentally augmented affinity, non-specific binding, spontaneous CAR clustering, and tonic signaling, all together relating to T cell functionality in an integrated fashion.
conclusionsData emphasize that tonic signaling is not always due to the positive charge but can be driven by hydrophobic interactions of the scFv. CAR binding affinity above the threshold and tonic signaling are required for sustained T cell functionality in antigen rechallenge and long-term tumor control.
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