Recent advances in molecular biology and immunology have resulted in a renewed interest in cancer vaccine development. Technical and theoretical problems leading to multiple failed vaccine trials, in the past, have now been better defined. We now know that human tumors are immunogenic and have identified a variety of proteins that act as tumor antigens. We have a more detailed understanding of T -cell-antigen recognition and the character of peptides presented in MHC molecules. Finally, mechanisms of tumor immune escape are much better understood, such as the role tolerance plays in dampening the tumor specific immune response and the importance of appropriate antigen presenting cells, such as dendritic cells, in initial immune stimulation. Current reported trials of cancer vaccines, are, at last, demonstrating the ability to elicit detectable immunity in patients immunized. A major problem now facing tumor immunologists is the standardization and development of reproducible and clinical grade immunologic assays to determine the magnitude of tumor specific immune responses generated in the context of human clinical trials. New technologies based on the function of antigen specific T cells, the recognition of peptide-MHC complexes, and the interaction of T helper cells with B cell augmentation have allowed the development of highly quantitative methods of T cell and antibody analysis based on antigen specific recognition and function. The purpose of this proposal is to develop these novel technologies for clinical use and apply these techniques in the monitoring of active cancer vaccine trials.
The specific aims of this proposal are to: (1) determine whether ELIspot analysis for the measurement of tumor antigen-specific T cells can act as a surrogate marker for predicting effective immunization after administration of a cancer vaccine, (2) determine whether flow cytometry for intercellular cytokine production by tumor antigen specific CD4 and CD8 T cells can act as a surrogate marker for predicting effective immunization after administration of a cancer vaccine, (3 ) determine whether Class I HLA-2 tetramers can be used for the measurement of tumor antigen-specific T cells and act as a surrogate marker for predicting effective immunization after administration of a cancer vaccine, and, finally, ( 4) to determine whether tumor antigen specific antibodies can act as a surrogate markers of effective immunization and/or reflect the development of a cancer specific T cell response.
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