A team led by Ludwig Lausanne’s Director George Coukos and Melita Irving, together with their colleague Bruno Correia of the École Polytechnique Fédérale de Lausanne, reported the design of a novel chimeric antigen receptor (STOP-CAR) in the February issue of Nature Biotechnology. The STOP-CAR system can be switched on and off on demand to prevent dangerous runaway immune responses and CAR-T cell exhaustion. By structure-based computational design, the researchers devised a strong interface between two human proteins: one natural, and the other a rationally modified scaffold to which it binds. This interface can, however, be dissociated by a specific small molecule. The proteins were then incorporated into a novel chimeric antigen receptor (CAR) design that placed the tumor-antigen binding part of the CAR on one chain and the T-cell signaling part—which functionally activates the CAR-T cell—on a second chain. Due to the interface, the two chains spontaneously associate and can activate their host CAR-T cells in response to antigen. But the activation can be switched off by the small disruptive molecule—and restored upon its removal. The system highlights the potential of structure-based design to add a layer of control to cellular immunotherapies. The researchers are now adapting their STOP-CAR for clinical use.
This article appeared in the August 2020 issue of Ludwig Link. Click here to download a PDF (2 MB).