A novel cancer vaccine was obtained by combining GM3 ganglioside with Neisseria meningitidis outer membrane protein complex to obtain very-small-size proteoliposomes (GM3/VSSP). The authors report the results of a phase 1 study of intramuscular administration of GM3/VSSP/Montanide ISA 51 to patients with metastatic melanoma. Twenty-six patients were included in three dose-level cohorts of 120, 240, and 360 mug. The first five doses (induction phase) were given at 2-week intervals, and the remaining four doses were given monthly. Patients were evaluated for dose-related toxicities and antitumor effects. In addition, serum and peripheral blood mononuclear cells were obtained at baseline and throughout treatment to evaluate humoral and cellular immune responses. One episode of severe hypotension and fever was observed in a patient included at the highest dose level. Other toxicities consisted of local reactions at the site of injection and mild fever and chills. Five doses of GM3/VSSP induced an anti-GM3 IgM response in 44% of patients. Serum reactivity was also observed against melanoma cell lines and tumor biopsies. GM3/VSSP was shown to induce very strong in vitro IFNgamma secretion in all evaluated melanoma patients. Furthermore, in one patient IFNgamma secretion was shown to be GM3-specific. A 62% reduction of a mediastinal mass was documented in one patient (partial response), while a second patient benefited from initial disease stabilization followed by tumor reduction in nonmeasurable soft tissue lesions accompanied by vitiligo.