Development of Survivin as a Vaccine Target for Pancreatic Cancer

描述(申请人提供)：胰腺癌(PC)是一种毁灭性的疾病，使用目前的化疗和放射治疗方案，总的五年存活率只有1-3%。迫切需要创造性和更新颖的治疗方法。针对过度表达的肿瘤特异性抗原的治疗性肿瘤疫苗的主动免疫治疗是一种新的、有前途的PC治疗方法。抗癌疫苗接种的目的是激活肿瘤抗原特异性的CD8+细胞毒性T淋巴细胞(CTL)，使其渗入肿瘤并杀死肿瘤。除了CD8+T细胞外，针对肿瘤抗原的CD4+T辅助细胞反应在增强和维持这些CTL反应方面起着至关重要的作用。我们的目标是开发一种治疗性疫苗方法，用于PC的临床测试。预计这些疫苗将被修改和/或与额外的免疫调节剂结合，以增强患者的抗肿瘤T细胞反应。为了开始这项研究计划，我们希望首先通过表征PC患者中现有的针对特定肿瘤相关抗原(TAA)的T细胞反应的性质来了解竞争环境，并确定用于疫苗接种的关键多肽表位。作为第一代靶点，我们瞄准的是Survivin基因。最近发现Survivin在许多癌症类型中高度过度表达，包括PC。它是肿瘤细胞存活所必需的凋亡抑制因子(IAP)家族的成员，尤其是在转移性疾病中。Survivin是一种理想的基于T细胞的PC免疫治疗靶点，不仅是因为这个原因，还因为它在肿瘤特异性的过度表达(80%的PC)，并在其他癌症中表现出免疫原性。我们建议在PC患者中鉴定CTL介导的针对Survivin的免疫应答的性质，并鉴定CD8+CTL识别的新的HLA类L结合多肽，为计划在PC患者中进行基于Survivin的治疗性疫苗试验做准备。同时，我们将从Survivin中识别新的HLA11类结合表位，以激活CD4+辅助反应，特别是那些受人类群体中高度代表的HLA-DP4和DRB1等位基因限制的表位。PC患者血清中针对Survivin的抗体反应也将被映射为与CD4+反应相关。我们的最终目标是将HLAII类和I类Survivin表位结合到疫苗中，以产生最大限度的CTL扩增和肿瘤杀伤。该项目中使用的表位识别技术也将在确定未来其他潜在的PC抗原方面发挥关键作用。

DESCRIPTION (provided by applicant): Pancreatic cancer (PC) is a devastating disease having an overall five-year survival rate of only 1-3% using present chemotherapy and radiation therapy protocols. There is a critical need for creative and more novel treatment approaches. A new and promising treatment for PC is active immunotherapy targeting over-expressed tumor-specific antigens with therapeutic cancer vaccines. The aim of anti-cancer vaccination is to activate tumor-antigen-specific CD8+ cytotoxic T lymphocytes (CTL) that infiltrate and kill tumors. In addition to CD8+ T cells, CD4+ T-helper responses against tumor antigens have emerged to be critical in augmenting and maintaining these CTL responses. Our goal is to develop a therapeutic vaccine approach for clinical testing in PC. It is anticipated that these vaccines will be modified and/or combined with additional immuno-modulators to boost anti-tumor T-cell responses in patients. To begin this research program, we want to first understand the playing field by characterizing the nature of existing T-cell responses against specific tumor-associated antigens (TAA) in PC patients and identify key peptide epitopes for vaccination. As a first-generation target, we are aiming at the Survivin gene. Survivin has recently been found to be highly over-expressed in many cancer types, including PC. It is a member of the inhibitors of apoptosis (IAP) family required for the survival of cancer cells, especially in metastatic disease. Survivin serves as an ideal T-cell-based immunotherapy target for PC not only for this reason, but also due to its tumor-specific over-expression (>80% of PCs) and demonstrated immunogenicity in other cancers. We propose to characterize the nature of CTL-mediated immune responses against Survivin in PC patients and identify novel HLA class l-binding peptides recognized by CD8+ CTL in preparation for a planned Survivin-based therapeutic vaccine trial in PC patients. In parallel, we will identify new HLA class ll-binding epitopes from Survivin that activate CD4+ helper responses, especially those restricted by the HLA-DP4 and DRB1 alleles highly represented in the human population. Antibody responses against Survivin in PC patient sera will also be mapped as a correlate for CD4+ responses. Our eventual aim is to combine HLA class II and class I Survivin epitopes in vaccines that will generate maximal CTL expansion and tumor killing. The epitope identification technology used in this project will also be critical in defining other future potential PC antigens.