LAUSR

Universal immune receptors represent a rapidly emerging form of adoptive T cell therapy with the potential to overcome safety and antigen escape challenges faced by conventional chimeric antigen receptor (CAR) T cell therapy. By decoupling antigen recognition and T cell signaling domains via bifunctional antigen-specific targeting ligands, universal immune receptors can regulate T cell effector function and target multiple antigens with a single receptor. Here, we describe the development of the SpyCatcher immune receptor, the first universal immune receptor that allows for post-translational covalent attachment of targeting ligands at the T cell surface through the application of SpyCatcher-SpyTag chemistry. The SpyCatcher immune receptor redirected primary human T cells against a variety of tumor antigens via the addition of SpyTag-labeled targeting ligands, both in vitro and in vivo. SpyCatcher T cell activity relied upon the presence of both target antigen and SpyTag-labeled targeting ligand, allowing for dose-dependent control of function. Mutational disruption of covalent bond formation between the receptor and the targeting ligand still permitted redirected T cell function but significantly compromised antitumor function. Thus, the SpyCatcher immune receptor allows for rapid antigen-specific receptor assembly, multi-antigen targeting, and controllable T cell activity.