PC-8 Novel chemoimmunotherapy combinations for pancreatic cancer

Abstract

Introduction: Pancreatic cancer (PC) is a devastating malignancy. It is usually diagnosed at an incurable stage and has the poorest of prognoses of any cancer. Despite its relatively low incidence, it is the fourth leading cause of cancer-related death. A few chemotherapies have shown modest efficacy but are associated with significant toxicities and development of tumour resistance. For these reasons the median survival after diagnosis is about 4.6 months, 18% of patients survive one year and less than 5% survive for 5 years. Without improvement in PC therapy it may soon become the second leading cause of cancer related deaths. Immunotherapies are beginning to show efficacy as first line therapies for a number of cancers but have yet to prove effective against PC. This is due to the dense desmoplastic stroma and immune suppressive microenvironment characteristic of advanced disease. Thus novel chemo-immunotherapeutic combinations will likely be required to target the tumour and its microenvironment to create the conditions in which immunotherapies, such as checkpoint inhibition, will be effective. The data presented here details the development of combination chemotherapy capable of killing tumour cells whilst increasing the immunogenicity of the tumour. Results: Combinations based upon the chemotherapeutic drug Gemcitabine were studied. Gemcitabine was combined with Zolodronic acid, Pomalidomide, Oxaliplatin and mycobacterial adjuvants. These combinations demonstrated increased cytotoxicity of pancreatic cell lines compared to single agent treatment. Gemcitabine increased markers of immune recognition on these cell lines independently of its cytotoxic properties whilst Oxaliplatin increased markers of immunogenic cell death and uptake of tumour cells into dendritic cells. Combination treatment was able to enhance dendritic cell maturation and the activation of CD8+ T-cells, measured as increases in the expression of IFN-γ. Discussion: Taken together the data presented here shows that gemcitabine based combinations exhibit superior in vitro cytotoxicity and immunogenic properties compared to single agent therapy. Each of these agents has previously been paired with gemcitabine for treatment of pancreatic cancer, demonstrating low toxicity and potential clinical efficacy. This supports their development as 3 or 4 agent combinations. Further research using pre-clinical pancreatic cancer models is planned including the use of checkpoint inhibition in combination with Chemoimmunotherapy.