Development of Survivin as a Vaccine Target for Pancreatic Cancer

描述（由申请人提供）：胰腺癌（PC）是一种毁灭性的疾病，使用目前的化疗和放疗方案，总体5年生存率仅为1-3%。迫切需要创造性和更新颖的治疗方法。一种新的和有希望的治疗前列腺癌的方法是主动免疫治疗靶向过表达的肿瘤特异性抗原与治疗性癌症疫苗。抗癌疫苗的目的是激活肿瘤抗原特异性CD8+细胞毒性T淋巴细胞（CTL）， CTL浸润并杀死肿瘤。除了CD8+ T细胞外，针对肿瘤抗原的CD4+ T辅助反应在增强和维持这些CTL反应中也起着关键作用。我们的目标是开发一种用于PC临床试验的治疗性疫苗方法。预计这些疫苗将被修改和/或与其他免疫调节剂联合使用，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患者中针对特定肿瘤相关抗原（TAA）的现有t细胞反应的性质来了解竞争环境，并确定疫苗接种的关键肽表位。作为第一代靶标，我们的目标是Survivin基因。最近发现Survivin在包括PC在内的许多癌症类型中高度过度表达。它是癌细胞存活所需的凋亡抑制剂（IAP）家族的一员，特别是在转移性疾病中。Survivin作为一种理想的基于t细胞的PC免疫治疗靶点不仅是因为这个原因，还因为它的肿瘤特异性过表达（约80%的PC）和在其他癌症中的免疫原性。我们提出在PC患者中表征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结合肽，为计划中的基于Survivin的PC患者治疗性疫苗试验做准备。同时，我们将从Survivin中发现新的HLA类ll结合表位，这些表位可以激活CD4+辅助反应，特别是那些受人类中高度代表的HLA- dp4和DRB1等位基因限制的表位。PC患者血清中针对Survivin的抗体反应也将与CD4+反应相关。我们的最终目标是在疫苗中结合HLA II类和I类Survivin表位，从而产生最大的CTL扩增和肿瘤杀伤。该项目中使用的表位鉴定技术也将对确定其他潜在的PC抗原至关重要。

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.