Investigating a rational combination of top-rakend immunotherapeutics to develop a novel and effective immunotherapy for pancreatic cancer.

Pancreatic cancer (PDAC) is the 3th leading cause of cancer related death in the western world and the incidence is still rising. Due to its rapidly progressive nature and lack of early symptoms, 80-90% of the patients present itself late with advanced or metastatic disease. This results in the worst 5-year survival of all cancers (7%).Current treatment options for PDAC are limited since only 10-20% of the patients is eligible for curative surgical resection. The remaining patient population is treated with gemcitabine which has only modest improvements in survival due to chemoresistance in the majority of patients. The promising advantages that have been made in several cancer types are in great contrast with the scarce therapeutic improvements in PDAC.The tumour microenvironment (TME) is believed to be a major confounding factor involved in failure of conventional therapies, as well as in targeted and immune therapy. A hallmark of this microenvironment in PDAC is the strong desmoplastic reaction, orchestrated by the pancreatic stellate cells (PSC), which results in a dense fibrotic/desmoplastic stroma that surrounds the pancreatic cancer cells (PCC). This stroma, which can cover more than 50% of the tumour, consists of extracellular matrix, activated PSC and a variety of immune cells such as macrophages, T-lymphocytes, dendritic cells and natural killer cells. By acting as a mechanical and functional shield to the tumour, it plays a central role in the development, progression and invasion of PDAC and also creates an immunosuppressive TME by secretion of immunosuppressive factors.Therefore, we will attack PDAC on both fronts being the cancer cells and its surrounding stromal shield. To achieve this, we will investigate a novel, highly potent combination immunotherapy for PDAC, consisting of both immune stimulatory as well as anti-immune suppressive agents.

Keywords:PANCREAS, IMMUNOTHERAPY, COMBINATION IMMUNOTHERAPY

Disciplines:Adaptive immunology, Innate immunity, Cancer biology, Cancer therapy