CTLA4 and metastatic melanoma: Although this novel approach of manipulating the immune system with monoclonal antibodies to generate an immune response was introduced by Chambers et al. in the 1990s [142], Hodi et al. were the first to publish the results of a landmark phase III trial showing a dramatic improvement in OS with the anti-Cytotoxic T-lymphocyte associated protein 4 (CTLA4) antibody ipilimumab in metastatic melanoma [143].