EXTH-49. INTRAVENOUS INJECTION OF ONCOLYTIC PICORNAVIRUS SVV-001 PROLONGS ANIMAL SURVIVAL IN A NOVELPANEL OF PATIENT-DERIVED ORTHOTOPIC XENOGRAFT MOUSE MODELS OF ADULT GLIOBLASTOMA

Abstract

BACKGROUND: Glioblastoma (GBM) is the most malignant and aggressive brain tumor. GBM is only minimally responsive to aggressive standard therapies. Seneca Valley virus (SVV-001) is a non-pathogenic oncolytic virus that can pass through the blood-brain barrier. In this study, we developed a new panel of patient derived orthotopic xenograft (PDOX) models to examine the efficacy of SVV-001 combined with irradiation. We also explored the mechanism of tumor cell infection with SVV-001 in malignant gliomas. MATERIALS AND METHODS: Surgical GBM tumor samples were obtained from 17 patients and directly implanted into the right cerebrum of NOD/SCID mice (1x105 cells suspended in 2 uL growth medium). In vitro antitumor activities of SVV-001 were examined in primary cultures, pre-formed neurospheres, and monolayer cells derived from PDOX models. In vivo therapeutic efficacy was examined by single I.V. injection of SVV-001 alone or administered in combination with radiation treatment of pre-formed xenograft tumors in permissive models. RESULTS: 8 out from 17 samples had confirmed tumor formation in mouse brains; 4 of these samples have since been serially sub-transplanted for a total of 5 generations, while 7 intracerebral xenografts are in generation 2. These xenograft models precisely replicated histopathologic characteristics of their parental human tumors. SVV-001 at a multiplicity of infection of 0.5 to 25 replicated in and effectively killed primary cultures, pre-formed neurospheres, and monolayer glioma cells derived from adult glioma xenograft models in vitro. A single I.V. injection of SVV-001 (1 × 1011 viral particles/ kg) administered immediately after radiation or 1 week after radiation led to the infection of orthotopic xenografts without harming normal mouse brain cells and resulted in significantly prolonged survival in permissive models. CONCLUSION: Our results demonstrated that SVV-001 possesses potent anti-tumor activity against adult malignant high-grade gliomas. This study provides a pre-clinical rationale that supports the consideration of SVV-001 for clinical trials against adult gliomas.