Recent experimental evidence suggests that therapeutic immunization for certain malignancies is a realistic approach. Pre-clinical models based upon immunization of tumor-bearing hosts with antigen-pulsed dendritic cells (DC) demonstrate that regression of established tumors can be induced. Tumor regression is dependent upon an intact immune system and is mediated by antigen specific CD8+ T lymphocytes. This proposal is built upon the premise that delivery of an immunogenic peptide vaccine with subsequent intensive immunologic monitoring is required to optimally elicit an effective T cell response capable of eradicating residual tumor. Compelling evidence suggests that immunogenicity correlates with peptide binding affinity for molecules encoded by the major histocompatibility complex. The principal goal of this study is to create better, more immunogenic vaccines for melanoma by designing peptide antigens modified in crucial (anchor) residues that affect binding affinity for HLA class I molecules. Melanoma antigen gp100 and Mart-1 anchor modified peptides will be used with DC in clinical immunization trials designed to optimize the in vivo generation of antigen specific CD8+ cytotoxic T lymphocytes. Immunologic, pathologic, as well as radiologic endpoints will be used to judge the efficacy of each peptide. Newer methodologies such as T cell receptor beta chain repertoire analysis and four color flow cytometry will be incorporated into vaccine trials for melanoma to allow more precise monitoring. Immunogenicity of selected peptides will be validated using HLA transgenic mice.
The specific aims of this application are: 1) to create anchor modified peptides of the gp100 melanoma antigen restricted by HLA-A2; 2) to identify HLA-B7 restricted epitopes of gp100 and Mart-1; 3) to develop better strategies to characterize human T cell activation and recruitment after DC vaccination. The issues addressed in this application are designed to provide a more detailed understanding of the relationship between cellular immunity, tumor regression, and clinical response.
| Carreno, Beatriz M; Becker-Hapak, Michelle; Linette, Gerald P (2009) CD40 regulates human dendritic cell-derived IL-7 production that, in turn, contributes to CD8(+) T-cell antigen-specific expansion. Immunol Cell Biol 87:167-77 |
| Linette, Gerald P; Zhang, Dongsheng; Hodi, F Stephen et al. (2005) Immunization using autologous dendritic cells pulsed with the melanoma-associated antigen gp100-derived G280-9V peptide elicits CD8+ immunity. Clin Cancer Res 11:7692-9 |
