2017 Synthetic Biology: Engineering, Evolution & Design (SEED)
Universal Chimeric Antigen Receptors for Multiplexed and Logic Control of T Cell Responses
Author
Wilson Wong - Presenter, Boston University
T cells expressing chimeric antigen receptors (CAR) have shown promises in clinical trials against various cancers, but can also have toxicities due to off-targeting and over-activation. To improve the specificity, flexibility, and precision of the CAR, we developed a split, universal, and programmable (SUPRA) CAR system composed of a universal receptor expressed on T cells and a tumor-targeting scFv adaptor molecule. The universal receptor is the fusion of intracellular signaling domains and a leucine zipper as the extracellular domain (zipCAR). The adaptor molecule is the fusion of a cognate leucine zipper and a scFv (zipFv). The scFv on the zipFv binds to the antigen and the leucine zipper binds and activates the zipCAR on the T cells. We showed that our system has an ON/OFF switch functionality, can flexibility tune T cell activation, and can sense multiple antigens to perform logic computations. By developing orthogonal SUPRA CAR systems, we showed that we can independently regulate multiple signaling pathways in the same cell, or separately control immune responses from different cell types. We envision that this work will provide much-needed tools to improve the safety and efficacy of cellular cancer immunotherapy.