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Gp100 is a melanocyte differentiation antigen that is often used in anti-melanoma therapies as an antigen and a target. Several gp100 derived peptides are restricted by HLA-A2, -A3, and -A24 molecules and have been shown to be immunogenic in peptide-based vaccines. Vaccination with gp100 derived epitopes and IL-2 has induced tumor regression in patients with advanced disease [108]. A recently performed immunization study in patients with metastatic disease compared vaccines based on HLA-A2-restricted peptides of MART-127_35, gp100209 217, and tyrosinase^ administered in combination with a low dose of GM-CSf. The results

established that the HLA-A2 restricted peptide gp-100209 217 is more immunogenic than the other melanoma peptide antigens [109]. One patient of 25 showed an overall survival of 3-year post-completed vaccination without disease progression. In another study performed on patients with unresectable or metastatic melanoma, immunization with a slightly modified HLA-A2-restricted gp100 (G280-9V) peptide loaded on autologous DCs, resulted in uniform immunogenicity. High-avidity CTLs, generated against the modified peptide, were capable of killing melanoma cells that co-expressed A*0201 and gp100 [110]. A study performed in a human-mouse chimeric model showed that the modification of the naturally occurring gp100 sequence enhanced the immunogenicity of the peptide epitope. The modified gp100 peptide showed a much slower dissociation rate from the HLA-A2-peptide complex than the bound natural peptide [111]. As an extension of the modified peptide strategy, PBMCs from vaccinated patients were expanded in vitro and used for adoptive therapy. While there was no clear clinical response, two patients developed autoimmunity against their melanocytes showing antigen-specific activity of the transferred cells [112]. Best results were derived from trials that recruited patients with early or minimal disease. A vaccination study in HLA-A2+ patients with completely resected non-metastatic melanoma, using a modified melanoma peptide, gp100209 2M and adjuvant, demonstrated significant increases in the frequency of IFN-gamma producing CD8+ T cells in 33 of 35 patients and durable presence of gp100209 2M-specific memory CD8+ T cells with high proliferative potential [113].

Overall, vaccination with gp100 melanoma peptides can mount a significant antigen-specific CD8+ T-cell immune response, but translation into a clinical response appears to be compromised by the immunosuppressive environment of an advanced disease. As in the case of the tumor antigens discussed previously, gp100 in its Mr. Hyde role may be in part responsible for creating this immunosuppressed state.

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