Developing Effective Salmonella-based Approaches to Treat Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is predicted to have the second highest incidence of fatalities among all solid tumor malignancies worldwide. Despite three decades of research focused on treating PDAC, the five-year survival rate is less than 6%, thus leaving much room for improvement. Historically, PDAC has been difficult to treat due to the absence of early detection methods resulting in clinical disease that is significantly advanced and characterized by immunosuppression, an extreme form of fibrosis known as desmoplasia, and metastasis to vital organs [1]. Current chemotherapeutic combinations, such as gemcitabine with Abraxane, have been shown to extend patient survival; however, they only do so by two to three months [2]. The newly released irinotecan liposome injection tested in pancreatic cancer patients is, at best, equal in efficacy to gemcitabine with Abraxane [3-5]. The low efficacy and high toxicity of chemotherapy has lead to innovative new strategies using immunotherapeutic approaches for treatment of PDAC. For example, the whole pancreatic cancer cell vaccine expressing human macrophage-colony stimulating factor (GM-CSF), known as GVAX, combined with a Listeriabased vaccine expressing the PDAC antigen mesothelian (CRS-207) shows promise in extending survival evidenced by both pre-clinical and preliminary clinical data [6]. Furthermore, antibody therapies targeting CTLA-4 and PD-1 have shown great benefit toward enhancing antitumor immunity resulting in tumor regression and extension of survival in other solid tumor models [7]. Despite these successes, there is a growing consensus that a “multipronged” approach to induce anti-tumor immunity and simultaneously targeting immune suppression and desmoplasia will have the greatest effect in eliminating PDAC. However, balancing such aggressive approaches with minimal toxicity to the patient will prove to be an incredibly daunting task.