Here we seek to understand the effect of systemically administered Vesicular Stomatitis Virus (VSV) on humans and against metastatic endometrial cancer. This project includes the first-in-human clinical trial of VSV engineered to encode human interferon ? (hIFN?) and the sodium iodide symporter (NIS). hIFN? codes for interferon (IFN) which protects normal cells from VSV effects and NIS enables tumor cells infected with the virus to concentrate various iodine isotopes which can allow for imaging of tumors infected with the virus. The virus being tested in this project is VSV-hIFN?-NIS. We selected VSV as the platform virus for this study because: 1) VSV is a non-lethal, non-human (livestock) virus with mild, if any, symptoms in natural human infections, 2) VSV exposure in the United States is rare with <5% of the population being seropositive, 3) VSV has been safely administered to >7500 humans as the platform virus for HIV and Ebola virus vaccine development, 4) preclinical studies have shown that VSV potently and rapidly kills endometrial cancer cells and tumors, 5) advanced stage and high grade endometrial cancers have been shown to express receptors from the low density lipoprotein receptor (LDLR) family that VSV utilizes for cell infection, 6) mouse and canine studies have established the safety and maximum tolerated dose (MTD) of VSV-hIFN?-NIS in those mammals, 7) mouse studies have shown that VSV-hIFN?-NIS localizes to cancer and can be detected via SPECT/CT imaging, and 8) a phase I trial of a similar virus strain, VSV-hIFN?, is currently being performed in human subjects. This project has incorporated real-time assessments of toxicity, tumor infectivity, and systemic immune responses to the virus and against endometrial cancer. The overarching goal is to generate a comprehensive understanding of the impact of systemic administration of the virus on the immunocompetent human and determine tumor-specific effects of virus infection. The three specific aims to be investigated in this project are: 1. Determine the safety, toxicity and tumor specificity of VSV-hIFN?-NIS when administered intravenously to patients with metastatic endometrial cancer. 2. To determine VSV-hIFN?-NIS replication pharmacokinetics, and shedding after virus administration and perform RNAseq and exome sequencing on tumor and normal tissues to test a novel gene panel as a biomarker for tumor response to the virus. 3. Determine the impact of intravenous VSV-hIFN?-NIS on adaptive immune responses against the virus, endometrial cancer antigens, and immunosuppressive mediators.
This project is designed to test a new systemic virus therapy for metastatic endometrial cancer. Endometrial cancer is the most common gynecologic cancer in the United States. Advanced stage and recurrent disease are highly lethal and new treatments are desperately needed. Virus therapy has been tested in human clinical trials in several cancers, including gynecologic cancers. We have previously shown that the Vesicular Stomatitis Virus (VSV) potently and rapidly kills endometrial cancer cells and tumors in laboratory experiments. VSV is a non-human virus that normally infects livestock; natural infections in humans are non-lethal, with mild or no symptoms. Prior exposure or infection is rare in the United States and mostly occurs in humans with close contact with livestock (farmers, veterinarians). We have engineered a strain of VSV that carries two human genes with it when it infects cells. The virus this project will study is VSV-hIFN?-NIS. The human interferon beta gene (hIFN?) codes for interferon (IFN) which protects normal cells from VSV effects, and the sodium iodide symporter (NIS) enables tumor cells infected with the virus to concentrate various iodine isotopes which can allow for imaging of tumors infected with the virus. This project includes: 1) a phase I clinical trial of intravenous VSV-hIFN?-NIS in humans with metastatic endometrial cancer in which we will assess safety and toxicity of the virus, determine the maximum tolerated dose of the virus in humans, determine whether tumors infected with the virus are able to be detected with imaging, and early assessment of the impact of the virus on cancer response; 2) studies on the patients enrolled in the trial that will determine the tumor gene signature, virus infectivity and its ability to replicate in tumor, and elimination from the human body; and 3) the impact of the virus on patients' immune responses to the virus and to proteins on endometrial cancer cells. This project will determine the safety profile of VSV-hIFN?-NIS when administered to human subjects and guide us in developing novel treatment(s) for metastatic endometrial cancer.
