Melanoma Vaccines with Peptides, Protein and Adjuvant

描述(申请人提供)：由于CD4+T细胞不仅对黑色素瘤患者的发育很重要，而且对抗肿瘤免疫反应的持久性也很重要，我们推测，未能刺激这种CD4+T细胞可能是以前的多肽疫苗没有在大量黑色素瘤患者中诱导肿瘤消退的原因之一。我们最近发现了一系列由CD4+T细胞识别的MHC II类黑色素瘤表位。特别是，我们已经确定了NY-ESO-1抗原的几个表位，NY-ESO-1抗原通常在包括黑色素瘤在内的多种肿瘤类型中表达。我们现在建议进行临床试验，以评估带有T辅助表位的癌症疫苗对黑色素瘤患者的体内疗效。我们提出的研究项目的基本原理如下：(1)整合T辅助表位的疫苗将最佳地刺激高亲和力的肿瘤反应性CTL反应，能够介导肿瘤的消退；(2)针对NY-ESO-1表位的T辅助和CTL反应不太可能被原位耐受，因为这种抗原在正常组织中不表达；(3)CpG寡核苷酸佐剂有望刺激浆细胞样树突状细胞(PDC)，从而产生强大的Th1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在体内的影响。我们提出了以下目标：(1)以CpG 7909为佐剂，在黑色素瘤患者中进行NY-ESO-1衍生多肽和重组NY-ESO-1蛋白的I-II期随机临床试验；(2)针对特定目标1，分析接受多肽或蛋白质疫苗的患者血液中CD8+和CD4+T细胞的表位特异性和功能；(3)研究CpG+多肽或蛋白疫苗接种后浆细胞样树突状细胞(PDCs)的运输和免疫刺激作用。虽然我们不能预测目标1中提出的临床试验的结果，但这些结果应该有助于更好地理解通过皮肤接种与CpG 7909相关的多肽和蛋白质疫苗的机制。总之，这些数据将表明AIM 1中的一种疫苗干预在促进抗NY-ESO-1 CTL反应方面是否优于其他干预措施。这些数据还将使我们能够定义可能与CpG佐剂协同的其他策略，以进一步改进旨在增强肿瘤反应性CD8+T细胞和Th-1型CD4+T细胞的发展和持久性的疫苗。

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.