{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T22:50:48Z","timestamp":1793832648160,"version":"4.6.1"},"reference-count":80,"publisher":"American Society of Hematology","issue":"25","license":[{"start":{"date-parts":[[2024,3,17]],"date-time":"2024-03-17T00:00:00Z","timestamp":1710633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,6,20]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>Chimeric 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 CD3\u03b6 (CD247) gene, functional CAR fusion-genes are generated that exploit the endogenous CD3\u03b6 gene as the CAR\u2019s 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, TCR\u03b3\/\u03b4 T cells, regulatory T cells, and NK cells. In T cells, CD3\u03b6 in-frame fusion eliminated TCR surface expression, reducing the risk of graft-versus-host disease in allogeneic off-the-shelf settings. CD3\u03b6-CD19-CAR-T cells exhibited comparable leukemia control to TCR\u03b1 chain constant (TRAC)-replaced and lentivirus-transduced CAR-T cells in\u00a0vivo. Tuning of CD3\u03b6-CAR-expression levels significantly improved the in\u00a0vivo efficacy. Notably, CD3\u03b6 gene editing enabled redirection of NK cells without impairing their canonical functions. Thus, CD3\u03b6 gene editing is a promising platform for the development of allogeneic off-the-shelf cell therapies using redirected killer lymphocytes.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2023020973","type":"journal-article","created":{"date-parts":[[2024,3,17]],"date-time":"2024-03-17T17:59:39Z","timestamp":1710698379000},"page":"2599-2611","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":54,"title":["Integration of <i>\u03b6<\/i>-deficient CARs into the <i>CD3<\/i>\n                  <i>\u03b6<\/i> gene conveys potent cytotoxicity in T and NK cells"],"prefix":"10.1182","volume":"143","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7721-7978","authenticated-orcid":false,"given":"Jonas","family":"Kath","sequence":"first","affiliation":[{"name":"1Berlin Center for Advanced Therapies, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Berlin, Germany"},{"name":"2Berlin Institute of Health Center for Regenerative Therapies, Berlin Institute of Health at Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0476-2807","authenticated-orcid":false,"given":"Clemens","family":"Franke","sequence":"additional","affiliation":[{"name":"1Berlin Center for Advanced Therapies, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Berlin, Germany"},{"name":"2Berlin Institute of Health Center for Regenerative Therapies, Berlin Institute of Health at Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9595-0185","authenticated-orcid":false,"given":"Vanessa","family":"Drosdek","sequence":"additional","affiliation":[{"name":"1Berlin Center for Advanced Therapies, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Berlin, Germany"},{"name":"2Berlin Institute of Health Center for Regenerative Therapies, Berlin Institute of Health at Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijie","family":"Du","sequence":"additional","affiliation":[{"name":"1Berlin Center for Advanced Therapies, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Berlin, Germany"},{"name":"2Berlin Institute of Health Center for Regenerative Therapies, Berlin Institute of Health at Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1385-5249","authenticated-orcid":false,"given":"Viktor","family":"Glaser","sequence":"additional","affiliation":[{"name":"1Berlin Center for Advanced Therapies, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Berlin, Germany"},{"name":"2Berlin Institute of Health Center for Regenerative Therapies, Berlin Institute of Health at Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4209-7248","authenticated-orcid":false,"given":"Carla","family":"Fuster-Garcia","sequence":"additional","affiliation":[{"name":"3Institute for Transfusion Medicine and Gene Therapy, Medical Center-University of Freiburg, Freiburg, Germany"},{"name":"4Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Freiburg, Germany"},{"name":"5Faculty of Medicine, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maik","family":"Stein","sequence":"additional","affiliation":[{"name":"1Berlin Center for Advanced Therapies, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Berlin, Germany"},{"name":"2Berlin Institute of Health Center for Regenerative Therapies, Berlin Institute of Health at Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana","family":"Zittel","sequence":"additional","affiliation":[{"name":"1Berlin Center for Advanced Therapies, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3719-6652","authenticated-orcid":false,"given":"Sarah","family":"Schulenberg","sequence":"additional","affiliation":[{"name":"2Berlin Institute of Health Center for Regenerative Therapies, Berlin Institute of Health at Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline E.","family":"Porter","sequence":"additional","affiliation":[{"name":"6Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Andersch","sequence":"additional","affiliation":[{"name":"7Department of Pediatric Oncology and Hematology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Berlin, Germany"},{"name":"8German Cancer Consortium, Partner Site Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8406-5412","authenticated-orcid":false,"given":"Annette","family":"K\u00fcnkele","sequence":"additional","affiliation":[{"name":"7Department of Pediatric Oncology and Hematology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Berlin, Germany"},{"name":"8German Cancer Consortium, Partner Site Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2959-1653","authenticated-orcid":false,"given":"Joshua","family":"Alcaniz","sequence":"additional","affiliation":[{"name":"9Experimental Pharmacology & Oncology Berlin Buch GmbH, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3880-1658","authenticated-orcid":false,"given":"Jens","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"9Experimental Pharmacology & Oncology Berlin Buch GmbH, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4302-3240","authenticated-orcid":false,"given":"Hinrich","family":"Abken","sequence":"additional","affiliation":[{"name":"10Division of Genetic Immunotherapy, Leibniz Institute for Immunotherapy, Regensburg, Germany"},{"name":"11Chair Genetic Immunotherapy, University of Regensburg, Regensburg, 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