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Evans Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008884","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2021,1,6]]},"abstract":"<jats:p>\n                    Cell-based therapies are emerging as effective agents against cancer and other diseases. As autonomous \u201cliving drugs,\u201d these therapies lack precise control. Chimeric antigen receptor (CAR) T cells effectively target hematologic malignancies but can proliferate rapidly and cause toxicity. We developed ON and OFF switches for CAR T cells using the clinically approved drug lenalidomide, which mediates the proteasomal degradation of several target proteins by inducing interactions between the CRL4\n                    <jats:sup>CRBN<\/jats:sup>\n                    E3 ubiquitin ligase and a C2H2 zinc finger degron motif. We performed a systematic screen to identify \u201csuper-degron\u201d tags with enhanced sensitivity to lenalidomide-induced degradation and used these degradable tags to generate OFF-switch degradable CARs. To create an ON switch, we engineered a lenalidomide-inducible dimerization system and developed split CARs that required both lenalidomide and target antigen for activation. Subtherapeutic lenalidomide concentrations controlled the effector functions of ON- and OFF-switch CAR T cells. In vivo, ON-switch split CARs demonstrated lenalidomide-dependent antitumor activity, and OFF-switch degradable CARs were depleted by drug treatment to limit inflammatory cytokine production while retaining antitumor efficacy. Together, the data showed that these lenalidomide-gated switches are rapid, reversible, and clinically suitable systems to control transgene function in diverse gene- and cell-based therapies.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.abb6295","type":"journal-article","created":{"date-parts":[[2021,1,6]],"date-time":"2021-01-06T15:12:07Z","timestamp":1609945927000},"source":"Crossref","is-referenced-by-count":269,"title":["Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide"],"prefix":"10.1126","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7071-5517","authenticated-orcid":true,"given":"Max","family":"Jan","sequence":"first","affiliation":[{"name":"Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA."},{"name":"Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA."},{"name":"Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, 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