ArticleFrontiers in immunology2022
Programmable Attenuation of Antigenic Sensitivity for a Nanobody-Based EGFR Chimeric Antigen Receptor Through Hinge Domain Truncation.
Article in Frontiers in immunology, 2022. 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, 29 citations in OpenAlex.
- Nanobody-based targeted cancer therapy and immunotherapy: fear not the future.Acta pharmacologica Sinica · 2026Review
- Human CD3 complex is required for the generation of T-cell receptor-like chimeric antigen receptor targeting WT1 in natural killer cells.Cancer immunology, immunotherapy : CII · 2026Article
- Engineering T cells with a membrane-tethered version of SLP-76 overcomes antigen-low resistance to CAR T cell therapy.Nature cancer · 2025Article
- Application of nanobody‑based CAR‑T in tumor immunotherapy (Review).International journal of molecular medicine · 2025Review
- Fine tuning towards the next generation of engineered T cells.Nature biomedical engineering · 2025Review
- Engineering CAR-T cells for solid tumors: bispecific antigen targeting, tumor microenvironment modulation, and toxicity control.Immunologic research · 2025Review
- Broadly reactive anti-VHH antibodies for characterizing, blocking, or activating nanobody-based CAR-T cells.Antibody therapeutics · 2025Article
- Nanobodies and their derivatives: pioneering the future of cancer immunotherapy.Cell communication and signaling : CCS · 2025Review
- Expanding the CAR toolbox with high throughput screening strategies for CAR domain exploration: a comprehensive review.Journal for immunotherapy of cancer · 2025Review
- Engineering the next generation of CAR T- cells: precision modifications, logic gates and universal strategies to overcome exhaustion and tumor resistance.Frontiers in oncology · 2025Review
- Non-signaling but all important: how the linker, hinge, and transmembrane domains in the CAR hold it all together.Frontiers in immunology · 2025Review
- Entinostat, a histone deacetylase inhibitor, enhances CAR-NK cell anti-tumor activity by sustaining CAR expression.Frontiers in immunology · 2025Article
- CD8α Structural Domains Enhance GUCY2C CAR-T Cell Efficacy.Cancer biology & therapy · 2024Article
- A Flow Cytometry-Based Method for Assessing CAR Cell Binding Kinetics Using Stable CAR Jurkat Cells.Bio-protocol · 2024Article
- Nonsignaling extracellular spacer regulates tumor antigen selectivity of CAR T cells.Molecular therapy. Oncology · 2024Article
- Discovery and preclinical development of a therapeutically active nanobody-based chimeric antigen receptor targeting human CD22.Molecular therapy. Oncology · 2024Article
- Bringing cell therapy to tumors: considerations for optimal CAR binder design.Antibody therapeutics · 2023Review
- Bispecific T-Cell Engagers and Chimeric Antigen Receptor T-Cell Therapies in Glioblastoma: An Update.Current oncology (Toronto, Ont.) · 2023Review
- Simultaneous engineering of natural killer cells for CAR transgenesis and CRISPR-Cas9 knockout using retroviral particles.Molecular therapy. Methods & clinical development · 2023Article
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Authors and funding
14 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Epidermal growth factor family receptor (EGFR) is commonly overexpressed in many solid tumors and an attractive target for chimeric antigen receptor (CAR)-T therapy, but as EGFR is also expressed at lower levels in healthy tissues a therapeutic strategy must balance antigenic responsiveness against the risk of on-target off-tumor toxicity. Herein, we identify several camelid single-domain antibodies (also known as nanobodies) that are effective EGFR targeting moieties for CARs (EGFR-sdCARs) with very strong reactivity to EGFR-high and EGFR-low target cells. As a strategy to attenuate their potent antigenic sensitivity, we performed progressive truncation of the human CD8 hinge commonly used as a spacer domain in many CAR constructs. Single amino acid hinge-domain truncation progressively decreased both EGFR-sdCAR-Jurkat cell binding to EGFR-expressing targets and expression of the CD69 activation marker. Attenuated signaling in hinge-truncated EGFR-sdCAR constructs increased selectivity for antigen-dense EGFR-overexpressing cells over an EGFR-low tumor cell line or healthy donor derived EGFR-positive fibroblasts. We also provide evidence that epitope location is critical for determining hinge-domain requirement for CARs, as hinge truncation similarly decreased antigenic sensitivity of a membrane-proximal epitope targeting HER2-CAR but not a membrane-distal EGFRvIII-specific CAR. Hinge-modified EGFR-sdCAR cells showed clear functional attenuation in Jurkat-CAR-T cells and primary human CAR-T cells from multiple donors
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