IMMUNIZATION OF MELANOMA PATIENTS WITH GANGLIOSIDES

四种神经节苷，GM2, GD2， GD3和9-0-乙酰GD3，以及高

Four gangliosides, GM2, GD2, GD3 and 9-0-acetyl GD3, and the high molecular weight melanoma chondroitin sulfate proteoglycan epitope (mel-CSPG) are prominent cell membrane components of melanoma that we have selected as potential targets for immunological control after active immunization. Of these, GM2 is most immunogenic, but reactivity with GM2 has been largely restricted to IgM antibodies in a pattern most consistent with GM2 acting as a T cell independent antigen. Consequently, we have screened in the mouse, a large number of newer methods for augmenting or replacing T cell help. The three most promising approaches have been selected for adjuvant clinical trials in AJCC Stage III melanoma patients: a potent new macrophage activator and B cell mitogen termed proteosomes, as adjuvant/vehicle used either alone or mixed with other adjuvants or mitogens; covalent attachment at high epitope density of ganglioside to KLH for induction of T cell help; and the use of anti-idiotypic antibodies with binding sites which are internal images of the immunogenic epitopes of GD3 and mel-CSPG. following immunization, the antibody response will be monitored with ELISAs, immune stains and assays on cultured melanoma cells, and the DTH skin test response against the immunogen and related epitopes will be measured. Our specific aims are: 1. Identify and perfect the approaches which most effectively induce antibodies and/or DTH against at least 3 of these 5 antigens. 2. Construct and test the immunogenicity of a polyvalent vaccine based on the findings in Aim 1 and optimize it with regard to dose, route and schedule. 3. Test this demonstrably immunogenic polyvalent vaccine in a larger therapy trial in patients with measurable disease.