Abstract 2568: Combination treatment of bevacizumab and oncolytic HSV armed with angiostatin show enhanced antitumoral and antiangiogenic effects
Authors: Zhang Wei , Fulci Giulia , Rabkin Samuel D. , Zhang Xiang , Martuza Robert L. 
Published: June 2012

Abstract
Background: Bevacizumab (Avastin), a monoclonal antibody that inactivates VEGF, was approved by US Food and Drug Administration as a single agent for treatment of recurrent glioblastomas (GBM). It prolongs progression-free survival and controls peritumoral edema. However, its effect on prognosis and overall survival remains to be determined. Angiostatin is a naturally occurring inhibitor of angiogenesis that was shown to inhibit growth of primary and metastatic tumors, but can not be delivered efficiently to GBM. Oncolytic viruses (OV) are promising agents for the treatment of GBM, whose therapeutic potential is not fully exploited due to infiltration of anti-viral macrophages. Treatment with anti-angiogenic factors was shown to increase replication and therapeutic capacity of OV. We hypothesized that combination of Avastin with an HSV OV (G47Δ) coding for angiostatin (G47Δ-angio) would enhance GBM treatment due to increased viral spread and delivery of angiostatin.
Materials & Methods: G47Δ-angio was constructed using the “flip-flop” HSV-BAC system. Expression of angiostatin was confirmed by western blot; in vitro matrigel endothelial tube formation assay was performed to test its anti-angiogenic potential. We confirmed the capacity of this virus to infect cancer cells and inhibit tumor angiogenesis in vivo, and determined therapeutic efficacy using both a subcutaneous and an intracerebral glioma model in mice. A control virus not carrying the angiostatin gene (G47Δ-empty) served as the negative control for all experiments. Avastin (5mg/kg) was delivered by i.v injection in intracerebral glioma model, started at Day 5 and followed by twice a week for consecutive 4 weeks. Tumor angiogenesis was determined by CD31 and VEGF staining, macrophages infiltration was detected by F4/80 staining. The overall survival of intracerebral glioma mice was followed up in G47Δ-angio, Avastin and combination (G47Δ-angio + Avastin) treatments.
Results: G47Δ-angio decreased endothelial tube formation in vitro and demonstrated potent antiangiogenic effects in vivo. In our subcutaneous tumor model, G47Δ inhibited tumor growth (n=7/group, P&lt;0.05) and in the intracranial glioma model, G47Δ extended survival (n=10/group, P&lt;0.05). Furthermore, the combination treatment (G47Δ-angio + Avastin) had the most significant antitumor and antiangiogenesis efficacy compared with either treatment alone (n=10/group, P&lt;0.05).
Conclusion: Our results demonstrate that G47Δ-angio could significantly enhance antitumor and antiangiogenic efficacy. Moreover, the combination treatment could further improve the antitumor and antiangiogenic efficacy in intracerebral glioma model in vivo. Hence, “Arming” HSV with an antiangiogenic gene that targets both the tumor cells and tumor vasculature is a promising therapy for use with Avastin treatment in clinical translation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2568. doi:10.1158/1538-7445.AM2011-2568