ArticleJournal for immunotherapy of cancer2023
HER2 and HLA-A*02 dual CAR-T cells utilize LOH in a NOT logic gate to address on-target off-tumor toxicity.
Article in Journal for immunotherapy of cancer, 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, 26 citations in OpenAlex.
- Recent advancements and persisting challenges in the evolution of next generation car t cell therapy for solid malignancies: a comprehensive review.Immunologic research · 2026Review
- Barriers and Blueprints: Next-Generation Engineering Strategies for CAR-T Cell Therapy in Gastrointestinal Tumors.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Chimeric antigen receptor-macrophages: A new paradigm for cell therapy.Bioengineering & translational medicine · 2026Review
- Immunotherapy resistance in colorectal cancer: therapeutic strategies and biomarker-guided approaches.Cancer cell international · 2026Review
- Structure-Function Insights into Immune Receptors Drive Innovation in CAR-T Cell Therapy.Current issues in molecular biology · 2026Review
- Optimizing next-generation CAR-macrophages against solid tumors: challenges and potential strategies.Journal of hematology & oncology · 2026Review
- Application of CAR-T therapy in solid tumors: current opportunities and challenges.Cancer gene therapy · 2026Review
- Advances and challenges of chimeric antigen receptor T cell therapy in digestive system malignancies.World journal of clinical oncology · 2026Review
- Obstacles and improvement strategies for CAR-T cell therapy in solid tumors.Discover oncology · 2026Review
- Engineering CAR-T cells for solid tumors: overcoming antigenic, trafficking, and microenvironmental barriers.Frontiers in immunology · 2026Review
- Advancements and expanding applications of CAR-T cell therapy.Frontiers in immunology · 2026Review
- CAR-T therapy: Advances in respiratory diseases.Chinese medical journal pulmonary and critical care medicine · 2025Review
- From Bench to Bedside: Emerging Paradigms in CAR-T Cell Therapy for Solid Malignancies.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- EF1α, rather than CMV promoter, is suitable for luciferase tag expression in target cells forMolecular therapy. Methods & clinical development · 2025Article
- Insights into next-generation immunotherapy designs and tools: molecular mechanisms and therapeutic prospects.Journal of hematology & oncology · 2025Review
- Transcriptomic and proteomic characterization of cell and protein biomarkers of checkpoint inhibitor-induced liver injury.Cancer immunology, immunotherapy : CII · 2025Observational
- Enhancing the physiological characteristics of chimeric antigen receptor natural killer cells by synthetic biology.Frontiers in immunology · 2025Review
- From spheroids to organoids: next-generation models for CAR-T cell therapy research in solid tumors.Frontiers in immunology · 2025Review
- Research progress on HER2-specific chimeric antigen receptor T cells for immunotherapy of solid tumors.Frontiers in immunology · 2025Review
- Advancements in cellular immunotherapy: overcoming resistance in lung and colorectal cancer.Frontiers in immunology · 2025Review
Corrections and comments
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Authors and funding
17 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundOne of the major challenges in chimeric antigen receptor (CAR)-T cell therapy for solid tumors is the potential for on-target off-tumor toxicity due to the expression of CAR tumor antigens in essential tissues and organs. Here, we describe a dual CAR NOT gate incorporating an inhibitory CAR (iCAR) recognizing HLA-A*02 ("A2") that enables effective treatment with a potent HER2 activating CAR (aCAR) in the context of A2 loss of heterozygosity (LOH).
methodsA CAR-T cell screen was conducted to identify inhibitory domains derived from natural immune receptors (iDomains) to be used in a NOT gate, to kill A2
resultsA leukocyte immunoglobulin-like receptor B1 (LIR1) iDomain iCAR was identified as most effective in regulating the cytotoxicity of a second generation HER2 aCAR. Target transfer experiments demonstrated that the 'on' and 'off' cell state of the LIR1 NOT gate CAR-T cell is both durable and reversible. Protection required iCAR signaling and was associated with reduced aCAR and iCAR surface expression. iCAR regulation was sufficient to generate high target specificity in a 3D adjacent spheroid assay designed to model the interface between clonal A2 LOH foci and normal tissue. However, we observed significant bystander killing of A2
conclusionsWe have preclinically validated an iCAR NOT gate technology broadly applicable for targeting HER2 expression in the context of A2 LOH. This approach is designed to prevent off tumor toxicity while allowing highly potent antitumor activity.
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