Researchers co-led by Ludwig Chicago’s Ainhoa Arina reported in a July publication in Science Advances their design and preclinical evaluation of a modular chimeric antigen-receptor (CAR)-T cell construct that is not only universal, tunable and controllable, but can also be readily and repeatedly redirected to new antigenic targets. The extracellular portion of the CAR construct is an engineered G protein variant (GA1) that is activated by binding to an antibody fragment (Fab) that has two functions: antigen recognition via its variable domain and binding to the GA1 through its constant domain. The researchers, including Ludwig Chicago Co-director Ralph Weichselbaum, showed that both binding affinities can be adjusted to modulate the intensity of the CAR-T cell responses. Since the Fab and GA1CAR are delivered separately, the therapy can be switched off by the removal of the Fab, which can also be engineered to enable personalized antigen targeting and changed at any time to target alternative antigens as tumors evolve. The researchers demonstrated the efficacy of GA1CAR T cells and the ability to redirect them to new targets in mouse models of breast cancer. They also showed that the unloaded GA1CAR T cells can remain dormant in animals and be reactivated on demand with an appropriate Fab in case of tumor rebound.
A universal chimeric antigen receptor (CAR)–fragment antibody binder (FAB) split system for cancer immunotherapy
Science Advances, 2025 July 4