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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 CRL4CRBN 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. Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.


Max Jan, Irene Scarfò, Rebecca C Larson, Amanda Walker, Andrea Schmidts, Andrew A Guirguis, Jessica A Gasser, Mikołaj Słabicki, Amanda A Bouffard, Ana P Castano, Michael C Kann, Maria L Cabral, Alexander Tepper, Daniel E Grinshpun, Adam S Sperling, Taeyoon Kyung, Quinlan L Sievers, Michael E Birnbaum, Marcela V Maus, Benjamin L Ebert. Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide. Science translational medicine. 2021 Jan 06;13(575)

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PMID: 33408186

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