Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide
Name
nihms-1682821.pdf
Description
Accepted version
Size
2.38 MB
Format
Adobe PDF
Checksum (MD5)
b8dfc6f0c7cafa0581e849ed289ee987
Author(s)
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
Date Issued
2021
Journal
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Version
Author's final manuscript
Abstract
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. CRBN
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1126/SCITRANSLMED.ABB6295
