ArticleNature communications2023
Complementarity-determining region clustering may cause CAR-T cell dysfunction.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 32 citations in OpenAlex.
- Multi-dimensional orchestration of binders for improved CAR-T immunotherapy.Cancer letters · 2026Review
- Sequence and structural determinants of efficacious de novo chimaeric antigen receptors.Nature biomedical engineering · 2026Article
- Design optimization of antibody-ligand motifs to enhance CAR-T redirection activity against solid tumors.Cell reports. Medicine · 2026Article
- Mapping the TCR landscape: computational tools empowering translational immunology and therapy design.Journal for immunotherapy of cancer · 2026Review
- Dynamic regulation of BACH2 enhances CAR T cell function.Molecular therapy. Oncology · 2026Article
- Revitalizing T cells: breakthroughs and challenges in overcoming T cell exhaustion.Signal transduction and targeted therapy · 2026Review
- Sequence and structural determinants of efficaciousbioRxiv : the preprint server for biology · 2025Article
- B7-H3 nanobody-based CAR T cells control multiple myeloma growth, while dual BCMA/B7-H3 CAR T cells overcome antigen escape.Journal of hematology & oncology · 2025Article
- Fine tuning towards the next generation of engineered T cells.Nature biomedical engineering · 2025Review
- From TCR fundamental research to innovative chimeric antigen receptor design.Nature reviews. Immunology · 2025Review
- An adjusted droplet digital PCR assay for quantification of vector copy number in CAR-T cell and TCR-T cell products.Immuno-oncology technology · 2025Article
- Current Advances and Challenges in CAR-T Therapy for Hematological and Solid Tumors.ImmunoTargets and therapy · 2025Review
- Frontiers of cytokine engineering in CAR cell therapy for cancer.Frontiers in oncology · 2025Review
- CD8α Structural Domains Enhance GUCY2C CAR-T Cell Efficacy.Cancer biology & therapy · 2024Article
- Integrating binding affinity and tonic signaling enables a rational CAR design for augmented T cell function.Journal for immunotherapy of cancer · 2024Article
- MAGE-A4 pMHC-targeted CAR-T cells exploiting TCR machinery exhibit significantly improved in vivo function while retaining antigen specificity.Journal for immunotherapy of cancer · 2024Article
- Conversion of anti-tissue factor antibody sequences to chimeric antigen receptor and bi-specific T-cell engager format.Cancer immunology, immunotherapy : CII · 2024Article
- Controlling CAR-T cell activity and specificity with synthetic SparX adapters.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Decoding and overcoming T cell exhaustion: Epigenetic and transcriptional dynamics in CAR-T cells against solid tumors.Molecular therapy : the journal of the American Society of Gene Therapy · 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
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Chimeric antigen receptor (CAR)-T cell therapy is rapidly advancing as cancer treatment, however, designing an optimal CAR remains challenging. A single-chain variable fragment (scFv) is generally used as CAR targeting moiety, wherein the complementarity-determining regions (CDRs) define its specificity. We report here that the CDR loops can cause CAR clustering, leading to antigen-independent tonic signalling and subsequent CAR-T cell dysfunction. We show via CARs incorporating scFvs with identical framework and varying CDR sequences that CARs may cluster on the T cell surface, which leads to antigen-independent CAR-T cell activation, characterized by increased cell size and interferon (IFN)-γ secretion. This results in CAR-T cell exhaustion, activation-induced cell death and reduced responsiveness to target-antigen-expressing tumour cells. CDR mutagenesis confirms that the CAR-clustering is mediated by CDR-loops. In summary, antigen-independent tonic signalling can be induced by CDR-mediated CAR clustering, which could not be predicted from the scFv sequences, but could be tested for by evaluating the activity of unstimulated CAR-T cells.
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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.