725. Seneca Valley Virus, a Novel Systemically Deliverable Oncolytic Virus for the Treatment of Small Cell Lung Cancer and Other Neuroendocrine Cancers

Abstract

Top of pageAbstract Virotherapy holds great promise for treating cancer because oncolytic (|[ldquo]|cancer killing|[rdquo]|) viruses, whether native and/or engineered, may be more efficacious and less toxic than alternative treatments, such as chemotherapy and radiation. While conceptually attractive, key hurdles remain before an oncolytic virus can be systemically administered both effectively and safely, the basis for a successful virotherapy based anti-cancer regimen for metastatic cancer. A novel oncolytic virus, Seneca Valley Virus (SVV), has been discovered which may overcome many of these hurdles. In vitro studies demonstrated that SVV elicited potent cytotoxicity to tumor cell lines with neuroendocrine cancer characteristics (e.g. SCLC, Wilms, retinoblastoma) but no cytotoxicity on 20 non-neuroendocrine cancer cell lines or 10 primary normal human cell types was detected. Replication of SVV correlated with the cytotoxicity results. There was over a 10,000 fold difference in the EC50 between permissive and non-permissive cell types. Interestingly, a murine neuroblastoma cell line with neuroendocrine properties derived from strain A/J mice was shown to support replication of SVV to the same degree as permissive human lines. This result and the epidemiology of SVV suggest that mice may be a relevant model to examine the toxicity of SVV. An acute toxicity study was performed in A/J mice. No abnormalities (serum chemistry, hematology, body weights, gross necropsy) were observed following systemic administration as high as 1014 vp/kg. SVV also exhibited no overt toxicity in two other different strains of mice at similar systemically administered doses. SVV has also been shown to eliminate pre-established xenograft SCLC tumors (|[sim]|150 mm3) in mice at doses as low as 108 vp/kg delivered via a single intravenous injection. In addition, preliminary evidence suggests that the majority of humans do not have neutralizing antibodies to SVV and SVV does not elicit hemagglutination of human erythrocytes. We have also demonstrated that SVV has a substantially longer circulating half-life in mice relative to Adenoviral vectors, perhaps as a result of not interacting with cells or components in the bloodstream. Finally, SVV has several other innate advantages that make it attractive as a therapeutic and as the basis for a technology platform. SVV appears to be a promising therapeutic for patients that possess cancers with neuroendocrine properties.