Development of Survivin as a Vaccine Target for Pancreatic Cancer

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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.