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Jan, Max; Scarfò, Irene; Larson, Rebecca C; Walker, Amanda; Schmidts, Andrea; Guirguis, Andrew A; Gasser, Jessica A; Słabicki, Mikołaj; Bouffard, Amanda A; Castano, Ana P; Kann, Michael C; Cabral, Maria L; Tepper, Alexander; Grinshpun, Daniel E; Sperling, Adam S; Kyung, Taeyoon; Sievers, Quinlan L; Birnbaum, Michael E; Maus, Marcela V; Ebert, Benjamin L
Science translational medicine, 01/2021, Letnik: 13, Številka: 575Journal Article
Cell-based therapies are emerging as effective agents against cancer and other diseases. As autonomous "living drugs," 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 E3 ubiquitin ligase and a C2H2 zinc finger degron motif. We performed a systematic screen to identify "super-degron" 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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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