CTLA4 and metastatic melanoma: In 2011, 3 years prior to the approval of nivolumab, an antibody drug targeting CTLA-4 (ipilimumab: another immune-checkpoint molecule primarily involved in the priming phase), was developed and approved by the FDA for the treatment of unresectable or metastatic malignant melanoma (approved in Japan in 2015) (8, 9) (Figure 1).