Background: Glioblastoma (GBM) is the most malignant and aggressive brain tumor, and survival of patients affected by GBM has remained virtually unchanged over numerous years. GBM is only minimally responsive to aggressive standard therapies including radical surgery and concurrent chemo-radiation treatment with temozolomide (TMZ). Seneca Valley virus (SVV-001) is a non-pathogenic oncolytic virus that can be systemically administered and 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 therapeutic efficacy of SVV-001 combined with irradiation. In addition, we explored the mechanism of tumor cell infection with SVV-001 in malignant gliomas.
Material and Methods: Surgical GBM tumor samples were obtained from 17 patients and directly implanted into the right cerebrum of NOD/SCID mice (1×105 cells suspended in 2 uL growth medium). Once tumor formation was confirmed, we performed H&E staining and IHC to determine the pathologic characteristics of the PDOX models over serial in vivo passages and compared with the matched patient tumors. 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 4 intracerebral xenografts are in generation 2. The tumorigenicity of 8 additional samples is pending. 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 mouse models. Additionally, SVV-001 injected immediately after radiation significantly improved the overall survival of animals compared to administration of the virus 1 week after radiation, indicating that dose timing was crucial for full efficacy of the combinatory therapy.
Conclusion: Our results demonstrated that SVV-001 possesses potent anti-tumor activity against adult malignant high-grade gliomas. Because this study was performed in a panel of patient tumor-derived orthotopic xenograft models, it provides a pre-clinical rationale that supports the consideration of SVV-001 for clinical trials against adult gliomas.
Citation Format: Huiyuan Zhang, Lin Qi, Yuchen Du, Mari Kogiso, Frank K. Braun, Sibo Zhao, Holly Lindsay, Nabil Ahmed, Akash J. Patel, Patricia A. Baxter, Jack M. Su, Xiao-nan Li. SVV-001 prolongs animal survival in PDOX adult GBM models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4390.