Studies of Attenuated Salmonella with IL-2 against pancreatic cancer

DESCRIPTION (provided by applicant): Pancreatic cancer is a devastating disease with an extremely poor prognosis and is the fourth leading cause of cancer-related deaths in the United States. Our laboratory has shown that one oral dose of an attenuated strain of Salmonella typhimurium genetically engineered to carry the human gene for interleukin-2 (IL-2) (Salmonella-IL2) in established murine models of neuroblastoma, metastatic osteogenic sarcoma, and adenocarcinomatous metastases of the liver is effective in significantly reducing the size, weight, and volume in locally advanced tumors and the numbers of metastatic deposits. Salmonella tends to accumulate in tumor tissue, yet the exact mechanisms by which Salmonella imparts its antitumor effects are unknown. We hypothesize that orally administered Salmonella containing the human IL-2 gene (Salmonella-IL2) will significantly decrease the size, weight, and volume of primary pancreatic adenocarcinoma in an established murine model. Furthermore, the mechanisms behind this tumor destruction are multimodal and may include (1) local augmentation of the cellular immune response, (2) activation of an apoptotic pathway in tumor cells, (3) deprivation of cellular nutrients, and (4) impairment of the vascular supply to the tumor. We have an established research collaboration with 3 experts in the field of pancreatic carcinoma (Dr. Selwyn M. Vickers, Dr. Ashok K. Saluja, and Dr. Christopher A. Klug), all proficient in various pancreatic cancer cell models. Thus, the overall goals of this research program are (1) to investigate the potential antitumor role of Salmonella-IL2 in established in vivo murine models of pancreatic cancer and (2) to elucidate the mechanisms by with Salmonella-IL2 imparts its antitumor effect. PUBLIC HEALTH RELEVANCE: The objective of this research program is to develop and study a novel form of oral biotherapy for the treatment of pancreatic cancer. We will give attenuated Salmonella typhimurium which carries the human gene for interleukin-2 to mice in models of both primary and metastatic pancreatic cancer. We will study the antitumor potential and mechanisms of this novel therapeutic agent.