A variety of immunotherapeutic approaches have shown activity in patients with metastatic
melanoma with the best results being observed with
interleukin 2 (IL-2). Follow-up data through 2004 confirm the durability of responses produced by the Food and Drug Administration-approved high-dose
IL-2 regimen in this patient population. Efforts to develop more tolerable and/or effective IL-2-based treatment regimens by either prolonged administration of lower doses or the combination of
IL-2 with other
cytokines,
monoclonal antibodies, or
vaccines have yet to produce results superior to those seen with high-dose
IL-2 alone. Recent investigations have suggested that, in some patients,
IL-2 may expand regulatory T-cell populations leading to immune tolerance rather than antitumor immunity. Efforts to shift this balance in favor of immune rejection by reducing the confounding effects of regulatory T cells on
IL-2 therapy or the use of novel and potentially more purely immunostimulatory
cytokines are ongoing. Despite promising phase 2 data, phase 3 studies have failed to show meaningful clinical benefit for the combination of
cytokines with cytotoxic
chemotherapy, so-called "biochemotherapy." Nonetheless, recent investigations with biochemotherapy followed by maintenance
immunotherapy suggest that biochemotherapy may still have a role as a "bridge to
immunotherapy" in some patients with rapidly progressive disease. Given the low number of patients achieving durable benefit with
cytokine-based
immunotherapy, considerable recent effort has focused on identifying predictors of therapeutic response. Investigations suggest that immune responsiveness may be predetermined by a tumor microenvironment conducive to immune recognition and the host propensity to develop autoimmunity. Efforts to understand and further define pretreatment predictors of response through the use of gene expression and proteomic techniques are ongoing and raise the potential for eventually limiting
cytokine-based
immunotherapy to those most likely to benefit.