Advances and perspectives in immunotherapy of melanoma

Immunotherapy using unspecific modulators has a long tradition in the adjuvant treatment of stage II/III melanoma. Interferon has shown a consistent effect on relapse-free survival independent of interferon dosage and duration. The results of the American Joint Committee on Cancer (AJCC) Melanoma Staging Database analysis led to a strict inclusion of additional prognostic risk factors such as ulceration of the primary and microscopic lymph node involvement explored by the sentinel node biopsy in the revised 2009 AJCC classification. These factors are now being increasingly included as stratification factors into clinical trials and yield a new hypothesis that primarily patients with both characteristics benefit from adjuvant interferon treatment. In the metastatic situation, interleukin-2 is the only immunotherapeutic agent approved by the Food and Drug Administration. In combination with interferon and/or with various chemotherapeutic agents, IL-2 is associated with substantial toxic effect and poor efficacy that does not improve overall survival (OS). Ipilimumab is a fully human, monoclonal antibody that blocks the cytotoxic T-lymphocyte antigen-4 and has recently been approved for metastatic melanoma based on two independent randomized phase III studies both demonstrating an improved OS rate after 1, 2, and 3 years compared with the control group. Based on this major step in treating metastatic melanoma, novel adjuvant strategies in stage III and combination therapies with targeted agents in stage IV are currently being explored.