HLA-A2 ASSOCIATED PEPTIDE EPITOPES FOR CTL ON MELANOMA

描述(改编自《调查者摘要》)：细胞毒性 抗人黑色素瘤的T淋巴细胞(CTL)识别一组 由与I类MHC分子相关的多肽组成的表位。 这些多肽表位来自许多细胞蛋白， 包括共享的黑素细胞分化抗原(MDA)酪氨酸酶， Gp100/PMel17、Mart-1/Melan-A和gp75/Trp-1。附加共享多肽 与人类白细胞抗原A2相关的表位和未知数量的唯一表位 仍有待确认。目前还不清楚免疫优势最强的 多肽都被鉴定出来了。拟议工作的目的是 将已知的黑色素瘤反应性CTL多肽表位扩大到 评估丙二醛多肽免疫反应的临床重要性，并 评价多肽类肿瘤疫苗在高危黑色素瘤患者中的应用。 具体目标如下：目标1：确定多肽表位 黑色素瘤反应性CTL。这将包括：(A)直接识别 人类黑色素瘤反应性CTL受HLA-A2或HLA-A3限制的表位， 使用细胞方法和串联质谱学的组合，以及 (B)确定CTL对定义的表位的反应性 黑色素瘤谱系蛋白。目的2：确定其临床意义。 已知的黑色素瘤HLA-A2限制性多肽表位的CTL反应 黑色素瘤患者的反应性CTL(A)检测p946和p946 来自黑素细胞组织分化抗原的其他多肽包括 由黑色素瘤反应性人CTL识别的正常黑素细胞； 确定黑色素瘤患者对这些多肽的CTL反应 与疾病分期及预后相关。目标3：确定 人类对特定黑色素瘤多肽的CTL反应是否可以增强 通过在佐剂环境中接种疫苗；(A)确定CTL 对多肽946的反应性可以通过接种以多肽为基础的疫苗来增强 疫苗，(B)确定接种牛痘疫苗是否构成 提供比优化的纯化多肽疫苗更强的免疫原性。

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.