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 ？帮手？T细胞在诱导和维持抗肿瘤反应中起着关键作用。到目前为止，由CD4+T细胞识别的II类限制性黑色素瘤表位的报道很少，还没有成功的免疫治疗方法来产生和刺激人类抗肿瘤的CD4+T细胞。CD4+T细胞识别由黑色素瘤细胞或抗原提呈细胞表面的II类分子提呈的肿瘤表位。这种表位的定义具有重要意义，因为它将允许开发新的疫苗试验，旨在通过体内精确的分析来诱导可测量的抗肿瘤反应。我们最近成功地识别了新的II类限制性黑色素瘤表位，并建立了实验策略，使我们能够在不久的将来识别其他新的表位。我们的长期目标是开发优化多肽疫苗所需的知识，以便在体内诱导抗肿瘤T细胞反应。这项应用的重点是确定能够刺激特定的高亲和力黑色素瘤反应性CD4+T细胞的最佳多肽序列。具体目的是(1)确定由NY-ESO-1基因编码的、由Th1型CD4+T识别的MHC II类限制性表位 从黑色素瘤患者的外周血淋巴细胞(PBL)中分离和鉴定识别NY-ESO-1衍生表位的Th2和Th0型CD4+T细胞；(3)识别基于原始序列的氨基酸(AA)替代的多肽类似物，以增强抗原识别，并剖析肿瘤反应性CD4+T细胞激活事件的诱导；利用这些工具，我们将准备前瞻性地分析黑色素瘤或其他NY-ESO-1表达的肿瘤患者的CD4+T细胞免疫反应，并将这些表位鉴定为非治疗方案中的疫苗成分。综上所述，这些数据将使我们更好地理解帮助者的角色。T细胞在体内的抗肿瘤反应，并在此基础上设计更有效的免疫治疗临床方案，以调节患者对体内此类表位的反应。

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.