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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,10,29]]},"abstract":"<jats:p>The ability to remotely control the activity of chimeric antigen receptors (CARs) with small molecules can improve the safety and efficacy of gene-modified T cells. Split ON- or OFF-switch CARs involve the dissociation of tumor\u2013antigen binding from T cell activation (i.e., CD3\u03b6) on the receptor (R-) and signaling (S-) chains, respectively, that either associate or are disrupted in the presence of a small molecule. Here, we have developed an inducible (i)ON-CAR comprising the anti-apoptotic B cell lymphoma protein 2 protein in the ectodomain of both chains which associate in the presence of venetoclax. We showed that inducible ON (iON)-CAR T cells respond to target tumors cells in the presence of venetoclax or the BH3 mimetic navitoclax in a dose-dependent manner, while there is no impact of the drugs on equivalent second generation-CAR T cells. Within 48 h of venetoclax withdrawal, iON-CAR T cells lose the ability to respond to target tumor cells in vitro as evaluated by Interferon-gamma (IFN\u03b3) production, and they are reliant upon the presence of venetoclax for in vivo activity. Finally, by fusing a degron sequence to the endodomain of the iON-CAR S-chain we generated an all-in-one ON\/OFF-switch CAR, the iON\u00d8-CAR, down-regulated by lenalidomide within 4 to 6 for functionally inactive T cells (no IFN\u03b3 production) within 24 h. We propose that our remote-control CAR designs can reduce toxicity in the clinic. Moreover, the periodic rest of iON and iON\u00d8-CAR T cells may alleviate exhaustion and hence augment persistence and long-term tumor control in patients.<\/jats:p>","DOI":"10.1073\/pnas.2405085121","type":"journal-article","created":{"date-parts":[[2024,10,25]],"date-time":"2024-10-25T12:10:21Z","timestamp":1729858221000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":31,"title":["Dual ON\/OFF-switch chimeric antigen receptor controlled by two clinically approved drugs"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1482-6731","authenticated-orcid":false,"given":"Greta Maria Paola","family":"Giordano Attianese","sequence":"first","affiliation":[{"name":"Ludwig Institute for Cancer Research Lausanne, Department of Oncology, University of Lausanne and Lausanne University Hospital, Lausanne 1011, 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