Approaches to augmenting the immunogenicity of melanoma gangliosides: from whole melanoma cells to ganglioside-KLH conjugate vaccines.

Gangliosides are neuraminic acid containing glycosphingolipids that are anchored into the lipid bilayer of the plasma membrane by their lipophilic ceramide moiety. They are overexpressed on tissues of neuroectodermal origin, particularly in tumors such as melanomas, sarcomas, neuroblastomas and astrocytomas. With the ganglioside-KLH plus immunological adjuvant QS-21 conjugate vaccine, GM2 and GD2 have been shown to be consistently immunogenic, inducing cytotoxic IgM antibodies in most patients. The immunogenicity of other gangliosides also expressed on melanoma cells such as 9-0-acetyl GD3 and GD3 lactone is currently being tested with this conjugate vaccine approach. From the initiation of our adjuvant vaccine trials in 1975 to the present, the immunogenicity of ganglioside vaccines has increased significantly as vaccine development has progressed. For instance, GM2 antibody responses increased from low titer IgM antibodies induced in occasional patients after whole cell vaccines, to moderate titer IgM antibodies in 86% of patients after GM2/BCG vaccines, to higher titer IgM antibodies in 100% of patients treated with the GM2-KLH plus QS-21 vaccine. These antibodies are capable of mediating complement mediated cytotoxicity of GM2 expressing melanoma cells in the majority of patients and such antibodies, whether naturally produced or vaccine induced, have been associated with a significantly improved disease-free and overall survival. An initial double-blind randomized trial in AJCC Stage III melanoma patients comparing GM2/BCG with BCG alone, demonstrated a 14% improvement in disease-free interval at 4 years and an 11% improvement in overall survival, though neither result achieved statistical significance. Based on these encouraging clinical results and the clearly improved immunogenicity of the GM2-KLH plus QS-21 vaccine compared to the previous GM2/BCG vaccine, the following two large clinical trials are anticipated to begin in 1995-1996. The GM2-KLH plus QS-21 vaccine will be tested in the intergroup setting by ECOG in 450 patients with AJCC Stage II or III melanoma who are free of disease after surgery. Also to be tested in a multicenter trial is a GM2-KLH plus GD2-KLH plus QS-21 vaccine in patients with high risk AJCC Stage II-IV sarcoma after surgical excision of all known disease.