Melanoma Vaccines with Peptides, Protein and Adjuvant

描述（由申请人提供）：由于CD 4 + T细胞不仅对于抗肿瘤免疫应答的发展而且对于抗肿瘤免疫应答的持续性都很重要，我们假设不能刺激这种CD 4 + T细胞可能是以前的肽疫苗在大量黑素瘤患者中不能诱导肿瘤消退的原因之一。我们最近确定了一系列的MHC II类呈递的黑色素瘤表位的CD 4 + T细胞识别。特别是，我们已经鉴定了几个来自NY-ESO-1抗原的表位，该抗原通常由广泛的肿瘤类型（包括黑色素瘤）表达。我们现在建议进行临床试验，以评估在黑色素瘤患者体内的肿瘤疫苗与辅助性T细胞表位的疗效。我们提出的研究项目的基本原理是几个方面的，并且可以陈述如下：（1）整合T辅助细胞表位的疫苗将最佳地刺激能够介导肿瘤消退的高亲合力肿瘤反应性CTL应答;（2）针对来自NY-ESO-1的表位的T辅助细胞和CTL应答不太可能被原位耐受，因为该抗原不被正常组织表达;（3）CpG寡核苷酸佐剂有望刺激浆细胞样树突状细胞（PDCs），产生强的Th 1型免疫;（4）现代免疫监测技术将使我们能够区分接种疫苗患者血液中的黑色素瘤特异性T细胞反应，使我们能够评估我们的疫苗策略的体内影响。我们提出以下目标：（1）以CpG 7909为佐剂，进行NY-ESO-1衍生肽与重组NY-ESO-1蛋白在黑色素瘤患者中的I-II期随机临床试验;（2）分析特异性目的1中接受基于肽或蛋白的疫苗的患者的血液中的CD 8+和CD 4 + T细胞的表位特异性和功能;（3）研究CpG +肽或蛋白免疫后浆细胞样树突状细胞（PDCs）的迁移和免疫刺激作用。虽然我们无法预测目标1中提出的临床试验的结果，但这些结果应有助于更好地理解与CpG 7909相关的皮肤肽基和蛋白质基疫苗接种黑色素瘤患者的机制。总之，这些数据将表明在促进抗NY-ESO-1 CTL应答方面，Aim 1中的一种疫苗接种干预是否上级其它干预。这些数据还将使我们能够定义可能与CpG佐剂协同作用的其他策略，以进一步改善旨在增强肿瘤反应性CD 8 + T细胞和Th-1型CD 4 + T细胞的发育和耐久性的疫苗。

DESCRIPTION (provided by applicant): As CD4+ T cells are important not only for the development but also for the persistence of the anti-tumor immune responses, we have hypothesized that the failure to stimulate this CD4+ T cells may be one of the reasons why previous peptide vaccines did not induce tumor regression in a large number patients with melanoma. We have recently identified a series of MHC class II-presented melanoma epitopes recognized by CD4+ T cells. In particular, we have identified several epitopes derived from the NY-ESO-1 antigen that is commonly expressed by a broad range of tumor types, including melanomas. We now propose to perform clinical trials to assess the in vivo efficacy of cancer vaccines with T-helper epitopes in patients with melanoma. The rationale for our proposed research project is several fold and can be stated as follows:(1) vaccines integrating T-helper epitopes will optimally stimulate high-avidity tumor-reactive CTL responses capable of mediating tumor regression; (2) T-helper and CTL responses against epitopes that derive from NY-ESO-1 are less likely to be tolerized in situ since this antigen is not expressed by normal tissues; (3) CpG oligonucleotide adjuvants are expected to stimulate plasmacytoid dendritic cells (PDCs) resulting in strong Th1-type immunity; (4) modern immunologic monitoring techniques will allow us to discriminate melanoma-specific T cell responses in the blood of vaccinated patients, allowing us to assess the in vivo impact of our vaccine strategy. We propose the following aims: (1) To perform a phase I-II randomized clinical trial of NY-ESO-1-derived peptides versus recombinant NY-ESO-1 protein in patients with melanoma, using CpG 7909 as adjuvant; (2) To analyze the epitope-specificities and functions of CD8+ and CD4+ T cells from the blood of the patients undergoing peptide or protein-based vaccines in the Specific Aim 1; (3) To study the trafficking and immunostimulatory effects of plasmacytoid dendritic cells (PDCs) following vaccination with CpG + peptides or protein. While we cannot predict the results of the clinical trial proposed in Aim 1, those results should facilitate a better understanding of the mechanisms underlying peptide-based and protein-based vaccination through skin in association with CpG 7909 for patients with melanoma. Altogether, these data will indicate whether or not one vaccination intervention in Aim 1 is superior to the others in promoting anti-NY-ESO-1 CTL responses. These data will also allow us to define additional strategies that may synergize with CpG adjuvants to further improve vaccines designed to enhance the development and durability of tumor-reactive CD8+ T cells and Th-1 type CD4+ T cells.