Melanoma has historically been considered a refractory disease with few if any options in the advanced/metastatic setting. Advances in both immune and genetically targeted treatment approaches have revolutionized the spectrum of treatment options for melanoma patients over the last several years. Recently, checkpoint inhibition has become a major focus in the immune-based therapy of cancer, especially melanoma. This concept involves inhibition of regulatory cell surface molecules which act normally to dampen or modulate T-cell activation. Cancer, including melanoma, takes advantage of this physiologic mechanism to turn off T-cell activation and prevent effective T-cell antitumor responses. Checkpoint inhibitors such as anti cytotoxic T-lymphocyte antigen 4 (anti-CTLA-4) and anti programmed death-1 (PD-1) can reverse this immune suppression and release T-cell activation. Nivolumab, a monoclonal antibody to the PD-1 receptor, promotes antitumor immunity by removing this key negative regulator of T-cell activation. In phase I/II studies, promising activity and safety have been observed and ongoing phase III trials are comparing nivolumab with other standard of care therapies (chemotherapy, ipilimumab). Efficacy may be even further increased when used in combination with ipilimumab (albeit with increased toxicity). In contrast to typical short-lived responses with cancer therapy in metastatic solid tumors, many responses induced by nivolumab appear durable. In this review, we discuss the evolution of immune therapy in melanoma leading to the development of nivolumab, the clinical experience with this agent, and its future development and clinical potential.
- checkpoint inhibitor
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