{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T02:39:36Z","timestamp":1788230376839,"version":"build-2803163510"},"reference-count":116,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2020,11,16]],"date-time":"2020-11-16T00:00:00Z","timestamp":1605484800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Immunoadoptive therapy with genetically modified T lymphocytes expressing chimeric antigen receptors (CARs) has revolutionized the treatment of patients with hematologic cancers. Although clinical outcomes in B-cell malignancies are impressive, researchers are seeking to enhance the activity, persistence, and also safety of CAR-T cell therapy\u2014notably with a view to mitigating potentially serious or even life-threatening adverse events like on-target\/off-tumor toxicity and (in particular) cytokine release syndrome. A variety of safety strategies have been developed by replacing or adding various components (such as OFF- and ON-switch CARs) or by combining multi-antigen-targeting OR-, AND- and NOT-gate CAR-T cells. This research has laid the foundations for a whole new generation of therapeutic CAR-T cells. Here, we review the most promising CAR-T cell safety strategies and the corresponding preclinical and clinical studies.<\/jats:p>","DOI":"10.3390\/ijms21228620","type":"journal-article","created":{"date-parts":[[2020,11,16]],"date-time":"2020-11-16T21:48:52Z","timestamp":1605563332000},"page":"8620","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Engineering Next-Generation CAR-T Cells for Better Toxicity Management"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8177-2640","authenticated-orcid":false,"given":"Alain E.","family":"Andrea","sequence":"first","affiliation":[{"name":"Laboratoire de Biochimie et Th\u00e9rapies Mol\u00e9culaires, Facult\u00e9 de Pharmacie, Universit\u00e9 Saint Joseph de Beyrouth, Beirut 1100, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrada","family":"Chiron","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, CNRS, INSERM, UTCBS, Unit\u00e9 des Technologies Chimiques et Biologiques pour la Sant\u00e9, F-75006 Paris, France"},{"name":"Clinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud, H\u00f4pital Kremlin-Bic\u00eatre, Assistance Publique-H\u00f4pitaux de Paris, 94275 Le-Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phanie","family":"Bessoles","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, CNRS, INSERM, UTCBS, Unit\u00e9 des Technologies Chimiques et Biologiques pour la Sant\u00e9, F-75006 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6988-7832","authenticated-orcid":false,"given":"Salima","family":"Hacein-Bey-Abina","sequence":"additional","affiliation":[{"name":"Universit\u00e9 de Paris, CNRS, INSERM, UTCBS, Unit\u00e9 des Technologies Chimiques et Biologiques pour la Sant\u00e9, F-75006 Paris, France"},{"name":"Clinical Immunology Laboratory, Groupe Hospitalier Universitaire Paris-Sud, H\u00f4pital Kremlin-Bic\u00eatre, Assistance Publique-H\u00f4pitaux de Paris, 94275 Le-Kremlin-Bic\u00eatre, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,16]]},"reference":[{"key":"ref_1","first-page":"154","article-title":"The Toxins of William B. 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