The only new systemic therapies for resectable high-risk and established metastatic melanoma over the past 30 years (IFN alpha 2B and IL-2) have been developed from immunological approaches to this disease. Vaccines comprised of lineage antigens associated with melanization are the focus of current efforts to induce more effective CD8 T cell responses to melanoma. Epitopes of the tyrosinase, gp100/HMB45, and Melan-A/MART-1 molecules that are recognized by CD8 T cells in the context of the MHC-class I allele HLA-A2 have been well defined, and modified to improve immunogenicity as prepared by the NCI for ECOG evaluation. The ECOG/NCI-C phase III intergroup trial E4697 tests these 3 antigens (with the Montanide ISA adjuvant) with or without GM-CSF in terms of survival and progression-free interval of resectable advanced stage III (N+) or stage IV (M+) metastatic melanoma patients. Neither multi-epitope peptide vaccines, nor GM-CSF have to date been studied as proposed here, in patients without evidence of disease, but at very high risk of relapse. The present application seeks support for analysis of CD8 and CD4 T cell responses as well as antibody responses to the peptide epitopes used for vaccination. Serial blood samples will be obtained from 400 HLA-A2+ participants to be evaluated for T cell responses by ELISPOT IFN gamma release assay, based on an extensive experience in peptide vaccine trials conducted at the University of Pittsburgh. CD4 T cell responses have only recently been identified to lineage antigens of melanoma, and the applicants have recently identified a new CD4 epitope of Melan-A/MART-1 recognized in the context of NLA DR4. CD8 response to the HLA-A2 epitope of this antigen is highly associated with CD4 response. CD4 epitopes of tyrosinase and gp100 have been defined by others, thus it is now possible to measure CD8 and CD4 T cell responses, as well as antibody responses induced by vaccination against the lineage antigens of melanoma. This analysis of CD4 and CD8 T-cell as well as B-cell (antibody) responses is proposed here, and will be performed in relation to assessment of the clinical efficacy of multi-epitope peptide vaccination and GM-CSF therapy. Knowledge of the immune responses to be analyzed here will accelerate progress in the development of vaccines for melanoma on other solid tumors.
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