Importantly, CRISPR/Cas9-mediated depletion of Cbl-b in sort-isolated PD-1+Tim3+ T cells could largely restore CD8+ effector functions and absence of Cbl-b (Cbl-b−/−) in CAR-T cells specific for the human carcinoembryonic antigen (hCEA) increased overall mice survival, enhanced anti-tumor activity, and resulted in less PD1+Tim3+-exhausted tumor infiltrating CAR-T cells when transferred to mice carrying hCEA-expressing MC38 tumors [131]. This evidence concerns the gene CBLB and neoplasm.