Sindbis Virus Platform Provides an Oncolytic-Virus-Mediated and Immunotherapeutic Strategy to Overcome the Challenging Microenvironment of Pancreatic Cancer

<b>Background/Objectives:</b> Our laboratory has been developing a Sindbis viral (SV) vector platform for treatments of several types of cancers. In this study, we assess treatment efficacy for metastatic and immunosuppressive pancreatic cancer. <b>Methods:</b> Orthotopic mouse models were generated by injection of tumor cells into the pancreatic parenchyma. Sindbis vectors were inoculated intraperitoneally. Imaging of tumors was performed by either MRI or in vivo imaging using luciferase. Flow cytometry, multi-immunofluorescence and elispot analysis were performed for certain tumors. <b>Results:</b> SV can infect and reduce pancreatic tumors in three mouse model systems: a model bearing human pancreatic tumors, a highly metastatic model, and a model that reflects the highly immunosuppressive, desmoplastic microenvironment common to human pancreatic cancer. <b>Conclusions:</b> Combination of SV vector expressing IL12 with an immune co-stimulatory agent, anti-OX40, can reduce tumors, facilitate an influx of immune response cells into the tumor microenvironment, and prevent tumors in mice rechallenged with tumor cells promising an effective treatment for pancreatic cancer.