Carbonneau, Seth, Sharma, Sujata, Peng, Liaomin, Rajan, Vaisakh, Hainzl, Dominik, Henault, Martin, Yang, Chian, Hale, Jacob, Shulok, Janine, Tallarico, John, Porter, Jeffrey, Brogdon, Jennifer, Dranoff, Glenn, Bradner, Jay, Hild, Marc and Guimaraes, Carla (2021) An IMiD-inducible degron provides reversible regulation for chimeric antigen receptor expression and activity. Cell Chemical Biology. ISSN 24519448

Abstract

The recent development of successful CAR (chimeric antigen receptor) T cell therapies has been accompanied by a need to better control potentially fatal toxicities that can arise from adverse immune reactions. Here we present a ligand-controlled CAR system, based on the IKZF3 ZF2 β-hairpin IMiD-inducible degron, which allows for the reversible control of expression levels of type I membrane proteins, including CARs. Testing this system in an established mouse xenotransplantation model for acute lymphoblastic leukemia, we validate the ability of the CAR19-degron to target and kill CD19-positive cells displaying complete control/clearance of the tumor. We also demonstrate that the activity of CAR19-degron can be regulated in vivo when dosing a US Food and Drug Administration-approved drug, lenalidomide.

Item Type:	Article
Keywords:	chimeric antigen receptor (CART) CRBN degron IMiD protein regulation
Date Deposited:	23 Feb 2021 00:45
Last Modified:	23 Feb 2021 00:45
URI:	https://oak.novartis.com/id/eprint/42557