Combination immunotherapy and radiation therapy strategies for pancreatic cancer-targeting multiple steps in the cancer immunity cycle

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, with its mortality rate approaching its incidence rate every year. Accordingly, much interest has been generated in harnessing the immune system in order to improve survival outcomes for these patients. Pancreatic cancer is not thought to be as immunogenic as other cancers that have seen promising results with immune checkpoint inhibitors alone, therefore likely several targets within the cancer-immunity cycle will need to be employed for successful treatment. We sought to investigate both the current state of the field in immunotherapy in PDAC with a special emphasis on combined approaches with radiation therapy (RT). We also summarized ongoing clinical trials that are examining the use of radiotherapy with other immune-stimulating agents in the treatment of PDAC. A PubMed and clinicaltrials. gov search was conducted using the following search terms, either alone or in combination: "pancreatic cancer", "immunotherapy", and "abscopal effect". Open clinical trials were reviewed and included if they involved both RT and other immune-stimulating agents. Pancreatic cancers tend to reside within immune-suppressive tumor microenvironments (TME), express PD-L1, and secrete several immuno-suppressive agents, such as TGF-B, IL-10, indoleamine 2,3-dioxygenase, galectin-1. Whole-cell vaccine therapies, peptide and protein vaccines, dendritic cell vaccines, and vaccines with microorganisms have been investigated by themselves with promising results. Open clinical trials are currently investigating the use of these vaccines, which increase antigen presentation, with treatments that stimulate release of tumor antigens including RT. There are currently at least 21 open clinical trials investigating the combination of RT with other immune-stimulating agents. The combination of RT and immunotherapy may be a promising avenue for PDAC treatment and deserves further research.