) Adenocarcinoma of the pancreas (pancreatic cancer) is the fifth leading cause of cancer death in the U.S. with a case-fatality rate > 90%. Radiation and chemotherapy are only palliative for advanced disease, and have only a small effect on disease-free survival following pancreaticoduodenectomy. Moreover, no methods are available for primary prevention or early screening. Therefore, more effective therapies are urgently needed. Paracrine cytokine tumor vaccines are a novel approach for activating antitumor immunity. This strategy can cure mice with a low burden of established tumor. This model simulates the micro-metastatic disease that is frequently encountered in patients. We recently completed a phase I trial of an autologous tumor vaccine genetically modified to secrete the cytokine, GM-CSF in patients with advanced renal cancer. GM-CSF vaccine produced both clinical and immunologic responses, warranting immediate evaluation for treatment of other incurable cancers. The major limitation to generalizing an autologous approach for the treatment of other types of cancer is the technical difficulty of expanding most human tumors cells, currently the only source of antigens for immune priming. Two recent findings now strongly support the immunologic rationale for studying allogeneic tumor vaccines. First, most human melanoma antigens are shared among over 50% of tumors. Second, allogeneic tumor cells can be used to activate antitumor immunity because professional antigen presenting cells of the host rather than the vaccinating tumor cells themselves prime T cells, the effectors of the antitumor immunity. We have developed and characterized allogeneic pancreatic lines that have been genetically-modified to secrete GM-CSF. This proposal will test the hypothesis that an allogeneic paracrine cytokine tumor vaccine can generate tumor-specific immunity in patients with pancreatic cancer. A phase I trial will be conducted to evaluate this approach for: 1) safety of administration including local skin toxicity and systemic autoimmunity, 2) induction of antitumor immune responses including delayed type hypersensitivity against autologous tumor cells and in vitro tumor-specific T cell activity, 3) clinical responses, Fifteen patients with stage 2 or 3 pancreatic cancer who have undergone pancreaticoduodenectomy will be enrolled. In addition, in vitro T cell lines will be developed using lymphocyte and tumor specimens obtained from patients following vaccination and used to identify and characterize the antigens against which the immune response is generated. The demonstration of successful immune priming with an allogeneic vaccine will lead to the generalizability of paractine cytokine tumor vaccines to other cancers including breast and prostate cancers. In addition, characterization of pancreatic tumor antigens may lead to the development of recombinant vaccines that can more efficiently activate antitumor immunity.
| Prendergast, George C; Jaffee, Elizabeth M (2007) Cancer immunologists and cancer biologists: why we didn't talk then but need to now. Cancer Res 67:3500-4 |
| Laheru, Dan A; Pardoll, Drew M; Jaffee, Elizabeth M (2005) Genes to vaccines for immunotherapy: how the molecular biology revolution has influenced cancer immunology. Mol Cancer Ther 4:1645-52 |
| Thomas, Amy Morck; Santarsiero, Lynn M; Lutz, Eric R et al. (2004) Mesothelin-specific CD8(+) T cell responses provide evidence of in vivo cross-priming by antigen-presenting cells in vaccinated pancreatic cancer patients. J Exp Med 200:297-306 |
| Jaffee, E M; Hruban, R H; Biedrzycki, B et al. (2001) Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol 19:145-56 |
