Peptide antigens presented by class I MHC molecules and recognized by cytotoxic T lymphocytes (CTL) have been defined for several infectious agents and tumors of both murine and human origin. These peptides represent attractive candidates for the development of therapeutic and/or prophylactic vaccines for diseases in which CTL play an important role, including cancer. The technology for appropriate delivery of peptide antigens is still new and undergoing rapid development, and no consensus methodology exists. In addition, while CTL responses against pathogens and tumors have been stimulated by many of these methods, there have also been numerous failures. One important factor in the use of peptide antigens is that their affinity for the presenting MHC molecule will influence the level at which they are presented by APC in order to stimulate a CTL response, as well as their display on an infected cell or a tumor. In this regard, a large set of peptide antigens that are the subject of a number of clinical trials are those that have been defined as CTL targets on human melanoma cells. However, most of these peptides have a relatively low affinity for the presenting molecule HLA-A*0201, and it is not clear how to deliver these antigens in order to stimulate the most effective CTL. In addition, reproducible and generally accepted criteria for the development of effective CTL in response to vaccination are not well established. Therefore, it is important to develop means of quantifying CTL activity that bear a direct relationship to therapeutic efficacy. Comprehensive evaluation of these issues in vaccine delivery methodology in early stage clinical trials is prohibitive because of the difficulty in enrolling significant numbers of patients in many different protocols and comparing results obtained by the use of different methods. Therefore, development of appropriate preclinical models is a desirable goal.
The specific aims of this proposal will lead to the definition of methodology to measure both CTL number and avidity, and the use of this methodology to evaluate the importance of these parameters in effective tumor-specific immune responses. In addition, the impact of peptide affinity for MHC molecules on both the stimulation of CTL and their effectiveness in tumor destruction will be examined systematically. These issues will be addressed through the development of a preclinical model that will allow the evaluation of effective immune responses to peptide antigens that are presented by human class I MHC molecules.
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