Previous attempts to therapeutically target MUC1 failed because they targeted the tandem repeat domain, which is shed from tumor cells. Cancer cells express a cleavage product, MUC1*, that is the growth factor receptor that mediates tumor growth. We have two MUC1*-targeting CAR Ts in clinical trials where one bears the Tyr to Phe “1XX” mutations that slow signaling and greatly increase in vivo persistence. Both CAR Ts recognize the tumor via an antibody that binds to a cryptic site, that is only revealed when the transmembrane cleavage product MUC1* unfolds after cleavage and release of the tandem repeat domain.
