Mouse Model for Antigen Specific Immunotherapy of Cancer

描述(由申请人提供)：用模拟表位增强T细胞对肿瘤相关抗原的反应，这是一种实用的临床策略，不需要识别个别肿瘤的特定抗原。采用这一策略的临床成功是有希望的，但并不一致。通过更好地了解多肽/MHC与TCR结合的参数以及有效的抗肿瘤反应所需的最佳T细胞谱系，这些方法可能会得到加强。我们的总体假设是，模拟表位可以被设计成有效地增强对肿瘤的免疫反应。利用小鼠肿瘤模型系统，我们将确定TCR-模拟表位/MHC复合体的亲和力增加是否与抗肿瘤活性的增加相关。此外，使用一种新的系统系统地筛选具有给定亲和力和刺激T细胞克隆能力的模拟表位文库，我们将确定有效模拟表位的其他特征。具体地说，我们将确定具有改变的TCR接触残基或具有相同的TCR接触残基，但与TCR接触的氨基酸侧链的旋转体改变的模拟表位在增强T细胞对肿瘤的反应方面是否更有效。最后，我们将确定激活更多样化的TAA特异性T细胞是否会增强抗肿瘤免疫。这些研究将有助于设计新的治疗策略，包括刺激免疫系统对肿瘤抗原的反应。

DESCRIPTION (provided by applicant): 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.