Optimization of Melanoma Vaccine with T Helper Epitope

描述（由申请人提供）：有越来越多的证据表明，CD 4 + T细胞或 ?帮手？T细胞在诱导和维持抗肿瘤应答中起关键作用。到目前为止，已经报道了很少的由CD 4 + T细胞识别的II类限制性黑素瘤表位，并且尚未成功开发出用于在人体中产生和刺激抗肿瘤CD 4 + T细胞的免疫抑制方法。CD 4 + T细胞识别由黑素瘤细胞或抗原呈递细胞表面的II类分子呈递的肿瘤表位。这些表位的定义是非常重要的，因为它将允许开发新的疫苗试验，旨在诱导抗肿瘤反应，这是可测量的，通过精确的体内测定。我们最近成功地确定了新的II类限制性黑色素瘤表位，并建立了实验策略，使我们在不久的将来，以确定其他新的表位。我们的长期目标是开发优化肽疫苗所需的知识，以诱导体内抗肿瘤T细胞应答。本申请集中于确定能够刺激特异性高亲合力黑素瘤反应性CD 4 + T细胞的最佳肽序列。目的：（1）鉴定NY-ESO-1基因编码的Th 1型CD 4 + T细胞识别的MHC Ⅱ类限制性表位 （2）分离和鉴定识别NY-ESO-1衍生表位的Th 2和Th 0型CD 4 + T细胞（3）鉴定基于原始序列的氨基酸（aa）取代的肽类似物以增强抗原识别，并分析肿瘤反应性CD 4 + T细胞活化事件的诱导;使用这些工具，我们将准备前瞻性地分析黑色素瘤或其他NY-ESO-1表达肿瘤患者的CD 4 + T细胞免疫应答，并使用待鉴定的表位作为免疫方案中的疫苗组分。综合起来，这些数据将使我们更好地了解的作用？帮手？T细胞在体内抗肿瘤应答中的作用，并基于体内调节患者对此类表位的应答来设计更有效的免疫治疗临床方案。

DESCRIPTION (provided by applicant): There is accumulating evidence that CD4+ T cells or ?helper? T cells play critical roles in the induction and maintenance of anti-tumor responses. Few class II-restricted melanoma epitopes recognized by CD4+ T cells have been thus far reported and no immunotherapeutic approach has yet been developed successfully in order to generate and stimulate anti-tumor CD4+ T cells in humans. CD4+ T cells recognize tumor epitopes presented by class II molecules at the surface of the melanoma cells or antigen presenting cells. The definition of such epitopes is of major importance because it will allow the development of new vaccine trials designed to induce anti-tumor responses, which are measurable, by precise assays in vivo. We have recently been successful in identifying novel class II-restricted melanoma epitopes and have established experimental strategies that will allow us in the near future to identify other novel epitopes. Our long-term goal is to develop the knowledge required for the optimization of peptide vaccines in order to induce antitumor T cell responses in vivo. This application focuses on determining the best peptide sequences capable of stimulating specific high-avidity melanoma-reactive CD4+ T cells. The specific Aims are (1) To identify MHC Class II-restricted epitopes encoded by the NY-ESO-1 gene and recognized by Th1- type CD4+ T cells generated from peripheral blood lymphocytes (PBL) of patients with melanoma; (2) To isolate and characterize the Th2 and Th0-type CD4+ T cells that recognize the NY-ESO-1 derived epitopes (3) To identify peptide analogues based on amino acid (aa) substitutions of the original sequence in order to enhance antigen recognition, and dissect the induction of tumor-reactive CD4+ T cell activation events; Using these tools, we will be prepared to prospectively analyze the CD4+ T cell immune responses of patients with melanoma or other NY-ESO-1-expressmg tumors and to use the epitopes to be identified as vaccine components in inimunotherapeutic protocols. Taken together, these data will allow us to better understand the role of ?helper? T cells in the anti-tumor responses in vivo and to design more effective immunotherapeutic clinical protocols based on the modulation of patients responses to such epitopes in vivo.