Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide

Sci Transl Med. 2021 Jan 6;13(575):eabb6295. doi: 10.1126/scitranslmed.abb6295.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Humans
  • Jurkat Cells
  • Lenalidomide*
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen*
  • T-Lymphocytes*
  • Ubiquitin-Protein Ligases


  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen
  • Ubiquitin-Protein Ligases
  • Lenalidomide