Advances in the treatment of metastatic melanoma: new immunomodulatory agents

Antibodies targeting ligand-receptor interactions that control activation and function of immune cell subsets such as dendritic cells (DCs) and in particular T cells have shown substantial promise for the treatment of unresectable or metastatic melanoma. The furthest in development, the antagonist anti-CTLA-4 antibodies, which block a key negative regulator of T-cell activation, have been shown to produce durable clinical responses in a small subset of patients. One of these antibodies, ipilimumab, also prolonged overall survival in two randomized phase III studies, leading to regulatory approval for marketing by the US Food and Drug Administration (FDA). Consistent with its mechanism of action, the major adverse events from anti-CTLA4 stem from immune-mediated inflammatory reactions. Paradigms for the administration of anti-CTLA-4 and newer immunomodulatory agents have evolved to effectively manage the adverse events and also to consider unique patterns and kinetics of tumor response. Early clinical studies of another antagonist antibody, which blocks the co-inhibitory receptor PD-1 on activated T cells, also are showing promising activity in metastatic melanoma. The clinical efficacy of cancer vaccines, which in broad terms also includes intratumorally administered agents designed to increase tumor immunogenicity, is being investigated in ongoing phase III trials, and various new agents are in earlier development, including newer cytokines and T-cell or DC co-stimulatory antibodies, some of which have already demonstrated clinical activity in advanced disease. Current data suggest that focusing development on agents countering immune suppression in the tumor microenvironment or blocking regulatory checkpoints to T-cell activation may have the greatest clinical yield. Combinations of immunomodulatory agents also may improve clinical activity, although possibly at a cost of greater toxicity. A major challenge for the field will be to develop predictive biomarkers of response, and to identify mechanisms of resistance to existing agents that can be addressed in subsequent clinical trials.