No systemic medical therapy has yet been proven to have a significant effect upon relapse and death associated with melanoma among patients with metastasis to regional lymph nodes. A large controlled adjuvant trial of two doses and durations of IFN alfa-2b has therefore been designed, and this ECOG trial (EST 1690) has been adopted as a melanoma intergroup trial (INT 2055). To date, there has been no compelling evidence to indicate the mechanism or dose-response relationship for IFN alfa-2 in any human solid tumor. In this proposal, we will determine the immunologic effects of adjuvant IFN alfa-2b in patients being treated in the context of EST 1690/INT2055 and also examine the direct antitumor effects of IFN alfa-2b upon autologous melanoma cells in vitro. Host immunologic responses and/or direct tumor cell effects will be examined for possible correlation with disease outcome in subjects receiving high-dose IFN, low-dose IFN, or no IFN. Median interval to relapse among control subjects is anticipated to be 12 months and to death is anticipated to be less than 18-24 months. We will obtain regional lymph node lymphocyte and tumor specimens and serial peripheral blood lymphocyte specimens from treated and control subjects. We will establish the immunomodulatory function of IFN alfa-2b upon T cell cytotoxic, proliferative and cytokine-releasing responses against autologous tumor of regional lymph node and peripheral blood lymphoid populations tested. The effects of IFN upon the phenotype and function of lymphoid populations will be defined before and during treatment in vivo. Tumor cells obtained at initial operation will be examined for direct growth inhibition, induction of histocompatibility and tumor antigens, and IFN-induced enzymes. Anticipated results of this study and a definition of the role of indirect and direct mechanisms of IFN alfa-2 will provide the key to optimizing therapy of melanoma and other tumors, not only with IFN but a range of other available biologic agents. The hypothesis underlying this proposal is that the therapeutic effect of IFN alfa-2b in high-risk melanoma is due to indirect immunomodulatory effects upon host T cell reactivity to melanoma, alone or in combination with induction of cell surface MHC Class I antigens. The effects of IFN upon specific MHC- restricted T cell or B cell antibody host responses to autologous melanoma will be analyzed in comparison to effects upon non-MHC-restricted NK activity or direct anti-proliferative effects of IFN upon melanoma as the chief competing hypothetical mechanisms. subjects participating in the intergroup adjuvant trial EST 1690/INT 2055 offer a unique resource for tumor cells, regional lymph nodes, and peripheral blood lymphocytes that will permit the analysis of the effect of dose of IFN upon host responses, as well as potential correlations with relapse and survival benefit from this therapy in a controlled trial.
