Pancreatic cancer remains one of the most lethal cancers and late detection renders most tumors refractory to conventional therapies. Development of cancer prophylaxis may be the most realistic option for improving the mortality of this disease. Here we develop a novel individualized prophylactic and therapeutic vaccination regimen using induced pluripotent stem cells (iPSCs), gene editing and tumor-targeted replicating oncolytic viruses. We created a Virus-Infected, Reprogrammed Somatic cell-derived Tumor cell (VIReST) regime. iPSCs from healthy cells were induced to pancreatic tumor cells using in situ gene editing via stable provision of KRAS G12D and p53 R172H tumor driver mutations. These cells were pre-infected with oncolytic Adenovirus (AdV) as prime or Vaccinia virus (VV) as boost, to improve vaccine immunogenicity, prior to delivery of vaccines in a sequential regime to young KPC transgenic mice, genetically programmed to develop pancreatic cancer,to prevent the disease development. Tumor cells pre-infected with oncolytic AdV as prime or VV as boost was the best regime to induce tumor-specific immunity. iPSC-derived tumor cells were highly related in antigen repertoire to pancreatic cancer cells of KPC transgenic mice, suggesting that an individuals' stem cells can provide an antigenically matched whole tumor cell vaccine. The VIReST vaccination primed tumor-specific T cell responses, resulting in delayed disease emergence and progression and significantly prolonged survival of KPC transgenic mice. Importantly this regime was well-tolerated and non-toxic. These results provide both proof of concept and a robust technology platform for personalized prophylactic cancer vaccines to prevent pancreatic malignancies in at-risk individuals. Copyright ©2019, American Association for Cancer Research.