Clinical and immunologic basis of interferon therapy in melanoma

Interferon alpha2b (IFN-alpha2b) at high dosage is critical to the reversal of signaling defects in T cells of melanoma patients, and to the durable effector (alpha DC1) polarization of dendritic cells. These immunoregulatory effects appear to be uniquely achieved with levels of IFN-alpha only attainable in vivo using the high-dose regimen of IFN-alpha2b (HDI). Three US cooperative group studies have evaluated the benefit of HDI as an adjuvant therapy for high-risk melanoma. All have demonstrated significant and durable reduction in the frequency of relapse, while the first and third trials have demonstrated significant improvements in the fractions of patients surviving compared with observation (E1684) or with a ganglioside vaccine (GMK, E1694). A meta-analysis of 13 randomized trials evaluating adjuvant IFN therapy has now also demonstrated significant benefits for IFN in terms of RFS and OS. Research of IFN-alpha in melanoma is now focused on identifying prognostic markers of outcome and predictors of therapeutic response.