HEG1 and malignant mesothelioma: In the case of SKM-CAR, which recognizes the malignant mesothelioma-specific modified HEG1 molecule, we showed that the tonic signal of SKM-CAR with the CD28 co-stimulatory domain induces the terminal exhaustion of CAR-T cells, whereas that of SKM-CAR with the 4-1BB co-stimulatory domain maintains CAR-T cells in the progenitor exhaustion stage (4).