ArticleBlood2024
Integration of ζ-deficient CARs into the CD3ζ gene conveys potent cytotoxicity in T and NK cells.
Article in Blood, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers.
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Who cites it
34 citing papers in PubMed, 37 citations in OpenAlex.
- Advances in natural killer cell immunotherapy for hematologic malignancies.Cancer biology & therapy · 2026Review
- Recent advances in molecular mechanisms to improve the efficacy of CAR-T cell therapy for viral diseases, cancer, and autoimmune diseases.Stem cell research & therapy · 2026Review
- From Delivery to Design: Site-Specific Genome Engineering for Next-Generation CAR T-Cell Therapy.Biomedicines · 2026Review
- Autoantibody-Based Models for the Diagnosis and Activity Assessment of Takayasu Arteritis.Journal of cardiovascular translational research · 2026Article
- 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
- Epigenetic editing balances TCR suppression and persistence in CAR T cells.Molecular therapy. Advances · 2026Article
- Strategies to eliminate native T cell receptors for adoptive T cell therapies.Molecular therapy : the journal of the American Society of Gene Therapy · 2026Review
- Co-editing of NKG2A and FAS increases long-term cytotoxic capacity and persistence of CAR NK cells.Molecular therapy. Oncology · 2026Article
- mRNA-based CAR T cell engineering: Unmodified mRNA enables high CAR expression without innate immune activation in T cells.Molecular therapy. Nucleic acids · 2026Article
- Avoidance of related donors in CAEBV with germline immune variants: long-termoutcome of matched unrelated donor HSCT - a case report.Annals of hematology · 2026Article
- CAR T cell-induced interferon gamma enhances MHC class I expression and sensitizes neuroblastoma to TCR-engineered T cell therapy.Frontiers in immunology · 2026Article
- Viral vector-free generation of orthogonal IL-2-responsive CAR T cells through gene editing of IL-2 and its receptor.Blood immunology & cellular therapy · 2025Article
- HLA matching or CRISPR editing of HLA class I/II enables engraftment and effective function of allogeneic human regulatory T cell therapy in a humanized mouse transplantation model.Nature communications · 2025Article
- Site-specific genome engineering of primary human natural killer cells for programmable anti-tumor function.bioRxiv : the preprint server for biology · 2025Article
- Next-generation multiplex-edited CAR-NK cells: more edits, more power?Journal for immunotherapy of cancer · 2025Article
- Effects of CRISPR-Cas9-mediatedMolecular therapy. Methods & clinical development · 2025Article
- The hidden risks of CRISPR/Cas: structural variations and genome integrity.Nature communications · 2025Review
- Single-stranded HDR templates with truncated Cas12a-binding sequences improve knock-in efficiencies in primary human T cells.Molecular therapy. Nucleic acids · 2025Article
- Optimizing viral transduction in immune cell therapy manufacturing: key process design considerations.Journal of translational medicine · 2025Review
- Tailoring CAR surface density and dynamics to improve CAR-T cell therapy.Journal for immunotherapy of cancer · 2025Review
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Authors and funding
24 authors at 10 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
abstractChimeric antigen receptor (CAR)-redirected immune cells hold significant therapeutic potential for oncology, autoimmune diseases, transplant medicine, and infections. All approved CAR-T therapies rely on personalized manufacturing using undirected viral gene transfer, which results in nonphysiological regulation of CAR-signaling and limits their accessibility due to logistical challenges, high costs and biosafety requirements. Random gene transfer modalities pose a risk of malignant transformation by insertional mutagenesis. Here, we propose a novel approach utilizing CRISPR-Cas gene editing to redirect T cells and natural killer (NK) cells with CARs. By transferring shorter, truncated CAR-transgenes lacking a main activation domain into the human CD3ζ (CD247) gene, functional CAR fusion-genes are generated that exploit the endogenous CD3ζ gene as the CAR's activation domain. Repurposing this T/NK-cell lineage gene facilitated physiological regulation of CAR expression and redirection of various immune cell types, including conventional T cells, TCRγ/δ T cells, regulatory T cells, and NK cells. In T cells, CD3ζ in-frame fusion eliminated TCR surface expression, reducing the risk of graft-versus-host disease in allogeneic off-the-shelf settings. CD3ζ-CD19-CAR-T cells exhibited comparable leukemia control to TCRα chain constant (TRAC)-replaced and lentivirus-transduced CAR-T cells in vivo. Tuning of CD3ζ-CAR-expression levels significantly improved the in vivo efficacy. Notably, CD3ζ gene editing enabled redirection of NK cells without impairing their canonical functions. Thus, CD3ζ gene editing is a promising platform for the development of allogeneic off-the-shelf cell therapies using redirected killer lymphocytes.
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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.