Open AccessReversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide
Author(s) -
Max Jan,
Irene Scarfò,
Rebecca C. Larson,
Amanda Walker,
Andrea Schmidts,
Andrew A. Guirguis,
Jessica A. Gasser,
Mikołaj Słabicki,
Amanda A. Bouffard,
Ana P. Castaño,
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
Publication year - 2021
Publication title -
science translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.819
H-Index - 216
eISSN - 1946-6242
pISSN - 1946-6234
DOI - 10.1126/scitranslmed.abb6295
Subject(s) - lenalidomide , degron , ubiquitin ligase , chimeric antigen receptor , cereblon , cancer research , in vivo , thalidomide , antigen , pharmacology , chemistry , ubiquitin , biology , immunology , immune system , multiple myeloma , t cell , gene , biochemistry , microbiology and biotechnology
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 CRBN 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.