HLA-A2 ASSOCIATED PEPTIDE EPITOPES FOR CTL ON MELANOMA

描述（改编自研究者摘要）：细胞毒性 T淋巴细胞（CTL）对人黑色素瘤反应，识别一组 表位由与I类MHC分子相关的肽组成。 这些肽表位来源于许多细胞蛋白， 包括共有的黑素细胞分化抗原（MDA）酪氨酸酶， gp100/Pmel 17、MART-1/Melan-A和gp75/trp-1。 额外的共有肽 表位和未知数量的HLA-A2相关的独特表位 仍有待确认。 目前尚不清楚免疫优势最强的 肽都已被鉴定。 拟议工作的目的是 扩展了已知的黑色素瘤反应性CTL的肽表位， 评估对MDA-肽的免疫应答的临床重要性， 评估基于肽的肿瘤疫苗在高危黑色素瘤患者中的应用。 具体目的如下：目的1：鉴定用于抗人胸腺嘧啶的肽表位。 黑素瘤反应性CTL 这将包括（a）直接查明 受HLA-A2或HLA-A3限制的黑素瘤反应性人CTL的表位， 使用细胞方法和串联质谱法的组合，和 (b)鉴定针对来自定义的表位的CTL反应性 黑色素瘤谱系蛋白。 目的2：确定临床意义 对已知的黑色素瘤HLA-A2限制性肽表位的CTL应答 黑素瘤患者中的反应性CTL（a），以确定p946和 其它来源于黑素细胞组织分化抗原的肽， 在正常黑素细胞上被黑素瘤反应性人CTL识别;（B） 确定黑色素瘤患者中CTL是否对这些肽产生应答 与疾病分期和预后相关。 目标3：确定 是否可以增强人对确定的黑素瘤肽的CTL应答 通过在佐剂环境中接种疫苗;（a）确定CTL是否 对肽946的反应性可以通过用基于肽的 疫苗，（B）确定用牛痘构建体接种是否 提供比优化的纯化肽疫苗更大的免疫原性。

DESCRIPTION (Adapted from the Investigator's Abstract): Cytotoxic T-lymphocytes (CTL) reactive against human melanoma recognize a set of epitopes that consist of peptides associated with class I MHC molecules. These peptide epitopes are derived from a number of cellular proteins, including the shared melanocytic differentiation antigens (MDAs) tyrosinase, gp100/Pmel17, MART-1/Melan-A, and gp75/trp-1. Additional shared peptide epitopes and an unknown number of unique epitopes that are HLA-A2-associated remain to be identified. It is not clear that the most immunodominant peptides have all been identified. The purpose of the proposed work is to expand what is known about peptide epitopes for melanoma-reactive CTL, to assess the clinical importance of immune responses to MDA-peptides, and to evaluate peptide-based tumor vaccines in patients with high risk melanoma. The Specific Aims are as follows: Aim 1: To identify peptide epitopes for melanoma-reactive CTL. This will include (a) direct identification of epitopes for melanoma-reactive human CTL restricted by HLA-A2 or by HLA-A3, using a combination of cellular methods and tandem mass spectrometry, and (b) identification of CTL reactivity against epitopes derived from defined melanoma lineage proteins. Aim 2: To determine the clinical significance of CTL responses to known HLA-A2-restricted peptide epitopes for melanoma reactive CTL in patients with melanoma (a) to determine whether p946 and other peptides derived from melanocytic tissue differentiation antigens are recognized on normal melanocytes by melanoma-reactive human CTL; (b) to determine whether CTL responses to these peptides in melanoma patients correlates with stage of disease and prognosis. Aim 3: To determine whether human CTL responses to a defined melanoma peptide can be augmented by vaccination in the adjuvant setting; (a) to determine whether CTL reactivity to peptide 946 can be enhanced by vaccination with peptide-based vaccines, (b) to determine whether vaccination with a vaccinia construct offers greater immunogenicity than an optimized purified peptide vaccine.