A Virus-Infected, Reprogrammed Somatic Cell–Derived Tumor Cell (VIReST) Vaccination Regime Can Prevent Initiation and Progression of Pancreatic Cancer

Abstract

Purpose: 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 mortality associated with this disease. Here, we develop a novel individualized prophylactic and therapeutic vaccination regimen using induced pluripotent stem cells (iPSC), gene editing, and tumor-targeted replicating oncolytic viruses. Experimental Design: 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 preinfected 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 and delay disease development. Results: Tumor cells preinfected with oncolytic AdV as prime or VV as boost were 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 individual's 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 nontoxic. Conclusions: These results provide both proof of concept and a robust technology platform for the development of personalized prophylactic cancer vaccines to prevent pancreatic malignancies in at-risk individuals.

Treatment and Prevention of Lung Cancer Using a Virus-Infected Reprogrammed Somatic Cell-Derived Tumor Cell Vaccination (VIReST) Regime

“…Lack of immunogenicity plays a central role in therapeutic tumor vaccine failure, thus provision of an effective adjuvant is critical for inducing robust anti-tumor immune activity, even within the pre-malignant environment. Virus-infected cell vaccines, whereby tumor cells are pre-infected with replicating tumor tropic virus prior to delivery as a vaccine, has previously been shown to induce strong anti-tumor immune reactions ( 23 ), and we have demonstrated that replicating oncolytic Vaccinia virus (VV) and Adenovirus (AdV) can induce the necessary danger signals and inflammatory environment required for anti-tumor immune induction ( 10 ). To validate their use in a lung cancer vaccination regime, we investigated the ability of VV and AdV to replicate in and kill iPSC-derived KP-LC cells in vitro .…”

“…However, our improved understanding of the fundamental processes underlying the cancer-immunity cycle has led to a resurgence of interest in developing cancer vaccination strategies, which will be underpinned by rational approaches to selection of tumor antigen targets and prevention of immune suppression. We have recently described a novel vaccination strategy for pancreatic cancer that overcomes current limitations of antigen selection by creating autologous cancer vaccines directly from stem cells ( 10 ). Using two common driver mutations, KRAS G12D and P53 R172H , we were able to replicate the transcriptome profile of cancer cells isolated from transgenic mice in our stem cell derived pancreatic cancer cells.…”

“…This demonstrates that the initiating mutations are less relevant to the ensuing accrual of passenger mutations than the epigenetics and lineage specialization of individual tumors. As driver mutations can be expected to have low immunogenicity, these passenger mutations must be key targets if vaccination strategies are to be successful ( 10 , 24 ). One of the most important aspects of this vaccination regime is the ability to apply entirely autologous vaccines early, or even prior to, disease development.…”

“…We have recently presented a novel, personalized prophylactic vaccination strategy for the prevention of pancreatic ductal adenocarcinoma (PDAC) development in which induced pluripotent stem cells (iPSCs) were induced to PDAC cells via stable knock-in of inactive KRAS G12D and p53 R172H prior to lineage differentiation and transformation ( 10 ). Importantly, we found that the derived murine tumor cells displayed high antigenic similarities to PDAC cell lines derived from the related KPC or KC transgenic mouse model, demonstrating that the process we used to generate autologous vaccination material was sufficient to model neo-antigen accrual, based on the genetic and epigenetic profile of autologous stem cells, during the earliest stages of tumorigenesis.…”

Human Vaccines & Immunotherapeutics: news

“…A personalized cell-based cancer vaccine delayed disease onset and progression in a mouse model of pancreatic cancer. 7 The vaccine consists of pluripotent stem cells engineered to harbor tumor-associated mutations in KRAS and p53 and infected with replicating oncolytic Adenovirus and Vaccinia virus. When infused back into the mouse in an individualized fashion, the cells induced tumor-specific T-cell responses and doubled survival.…”