Rational Design of Peptide-Based Tumor Vaccine

描述（由申请人提供）：接种与肿瘤相关抗原（TAAs）衍生的t细胞反应片段相对应的合成肽可以增强表达相同抗原的患者的抗肿瘤免疫。人们越来越多地认识到，与病毒来源的表位相比，TAA表位通常与MHC分子结合较弱，因此无法在体内引起强大的T细胞反应。改善MHC结合作为一种上调抗原识别的策略，对癌症的免疫干预具有明确的意义。在过去的二十年中，在结构水平上对MHC/肽相互作用的理解取得了进展，这使得基于共同构象特征识别新的结合基序成为可能。

DESCRIPTION (provided by applicant): Vaccination with synthetic peptides corresponding to T-cell reactive fragments derived from tumor associated antigens (TAAs) can bolster anti-tumor immunity in patients expressing the same antigen. It has been increasingly acknowledged that TAA epitopes, in contrast to epitopes of viral origin, generally bind weakly to the MHC molecule and are therefore unable to elicit robust T cell response in vivo. Improving MHC binding as a strategy to upregulate antigen recognition has clear implications for immune intervention of cancer. Advances in the understanding of MHC/peptide interactions at the structural level over the past two decades have allowed the possibility of identifying novel binding motifs based on common conformational features. Analyses of the A2 molecule suggest a water-filled MHC/peptide binding interface. A direct implication of these studies is that hydrophilic amino acids in the central part of the bound peptide can indirectly interact with the MHC molecule and may modulate interactions with the T cell receptor. An Experimental Plan with two aims is proposed to: (i) study the pairwise interaction between two central residues in the MAGE-A4 epitope GVYDGREHTV on the diversity of TCR Vbeta CDR3 usage. (ii) derive and apply a common structural feature seen in eighteen x-ray structures to design of epitopes derived from Melan-A/MART-1, Her-2/neu, MUC1, CEA, MAGE-3, and AFP. As an outcome of the research proposed here, we expect to identify novel peptide sequences that are suitable as vaccine candidates in tumor immunotherapy. The research proposed in this application is significant, because upon successful completion, it will provide new criteria for converting low affinity TAA epitopes into high affinity variants that may recruit additional antigen-specific CTLs in vivo. By defining additional levels of sophistication of MHC/peptide/TCR interactions, more accurate predictions of immunogenic peptides will be possible. The research proposed will also benefit the development of peptide-based vaccines for viral and microbial infections.