Boosting the T cell response for tumor-associated antigens with mimotopes, peptide mimics of antigens, is a practical clinical strategy that does not require the identification of specific antigens for individual tumors. Clinical success employing this strategy has been promising, but inconsistent. Such approaches may be enhanced by a better understanding of the parameters of peptide/MHC binding to the TCR and the optimal T cell repertoire required for effective antitumor responses. Our overall hypothesis is that mimotopes can be designed to efficiently augment the immune response to tumors. Using a mouse tumor model system, we will determine whether increased affinity of the TCR-mimotope/MHC complex correlates with increased antitumor activity. In addition, using a new system to systematically screen a library of mimotopes of a given affinity and capacity to stimulate T cell clones, we will determine other characteristics of effective mimotopes. Specifically, we will determine whether mimotopes with either altered TCR-contact residues or with the same TCR-contact residues, but altered rotomers of the amino acid side chains that contact the TCR, are more efficient in augmenting the T cell response to tumors. Finally, we will determine whether activating a more diverse TAA-specific T cell repertoire will boost antitumor immunity. These studies will contribute to the design of new therapeutic strategies that involve stimulating the immune system to tumor antigens. ? ?
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