g(m3)-ganglioside and Skin-Diseases

NeuGcGM3 ganglioside is especially attractive because it is expressed on melanoma cells but it is minimally or not expressed at all on most normal human tissues. A Phase Ib/IIa clinical trial was carried out in patients with advanced cutaneous and ocular malignant melanomas, to evaluate immunogenicity and toxicity of an intramuscularly administered cancer vaccine and composed by NeuGcGM3 in a proteoliposome of Neisseria meningitides with Montanide ISA 51 as adjuvant. Twenty two patients were included, twelve at dose level of 200 microg and 10 at 400 microg. The first five doses were administered every other week and then monthly until 9 doses. 12 patients received additional immunizations. Vaccination induced specific anti-NeuGcGM3 IgM, IgG and IgA antibodies responses. Titers of IgM were greater for the highest vaccine doses. Vaccination also elicited DTH response in 45.5% of patients in the lower doses and 77.8% in the higher doses. Toxicities were mostly grade 1 or 2, according CTC-NCI criteria. Interestingly, 3 patients developed vitiligo at the lower dose (none in the highest dose) although the nominal antigen NeuGcGM3 is not present in melanocytes. Survival analysis was not the goal of this Phase I trial; nevertheless, the fact that seven patients are alive for more than 2 years after inclusion is noteworthy. Safety and immunogenicity with NeuGcGM3 vaccine treatment in advanced melanoma patients were established. The prognostic value of autoimmunity and the possibilities of dissociating anti-tumor immunity from autoimmunity deserve further research.

Topics: Adult; Aged; Bacterial Outer Membrane Proteins; Cancer Vaccines; Eye Neoplasms; Female; G(M3) Ganglioside; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Liposomes; Male; Mannitol; Melanoma; Middle Aged; Neisseria meningitidis; Oleic Acids; Skin Diseases; Survival Analysis; Treatment Outcome; Vaccination; Vitiligo

We have investigated the distribution of ganglioside GM3 in normal skin with 8G9D8, a monoclonal antibody against GM3, and found binding to the stratum corneum. By electron microscopy, strong deposition of antibody was seen at the corneocyte envelope/"plasma membrane" region. Significantly decreased to absent binding to the stratum corneum was shown in a variety of disorders of excessive keratinocyte proliferation, including squamous cell carcinomas, psoriasis, and bullous and non-bullous forms of congenital ichthyosiform erythrodermas, as well as in the hyperplastic cornoid lamellae of porokeratosis. The 8G9D8 antibody recognizes the carbohydrate sequence N-acetylneuraminic acid alpha 2----3 galactose beta 1----4 glucose (or N-acetylglucosamine). Thus, in addition to ganglioside GM3, 8G9D8 may bind to glycoproteins or another glycolipid of the stratum corneum with a shared carbohydrate sequence. The carbohydrate sequence recognized by 8G9D8, whether attached to an epidermal glycoprotein or glycolipid, may prove to be important in keratinocyte proliferation and differentiation.

Topics: Antibodies, Monoclonal; Cell Division; Epidermis; G(M3) Ganglioside; Gangliosides; Humans; Immunologic Techniques; Microscopy, Electron; Reference Values; Skin; Skin Diseases