CTLA4 and metastatic melanoma: Because each of these two proteins can inhibit activation of T-cells and down-regulate the immune response, the abnormal expression of CTLA-4 and PD-1 in tumor cells is suggested as a molecular mechanism of immune evasion in tumors.133 Ipilimumab, a CTLA-4 monoclonal antibody, was approved by the FDA for treatment of patients with metastatic melanoma (Table 4).134, 135 The PD-1 monoclonal antibodies, nivolumab136–138 and pembrolizumab,139 were also effective against metastatic melanoma (Table 4).