Vascular Biogenics Ltd (VBLT)

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VB-111 for brain cancer

Glioblastoma (GBM, WHO grade IV) is the most common and aggressive of the primary brain tumors in adults, with poor prognosis despite intervention with surgery, radiation and chemotherapy. Annually, 5 in 100,000 people are diagnosed with GBM, with a median survival of approximately 14 months. The low survival is attributed partly to the nature of the tumor. GBMs are highly vascularized tumors and display markedly disorganized vascular structures with conspicuous endothelial cell proliferation, pericyte and basement membrane abnormalities resulting in permeability with heterogeneous leakiness and abnormal blood flow. The location of the tumor also makes drug delivery difficult with only small or lipophilic molecules able to cross the blood brain barrier. Of those agents that are able to reach the tumor, GBMs have shown to be resistant to most cytotoxic agents and quickly develop resistance when initially sensitive.

Antiangiogenic therapy has rapidly evolved into an integral component of standard therapy for many malignancies. As an example, bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), was the first antiangiogenic drug to receive approval and is now considered a component of standard of care for ovarian, lung, kidney, colon and brain cancers. Yet, while antiangiogenics have improved the practice of clinical oncology, clinical outcomes suggest that these therapeutics only prolong overall survival of cancer patients by several months, without offering enduring cure. This may be in part due to tumor cells evading angiogenic inhibitors through modulation of collateral pathways. To overcome the limitations of existing antiangiogenic drug therapies, which ultimately fail, we assessed the efficacy of using VB-111 to target newly formed blood vessels. VB-111 is a nonreplicating adenovirus 5 (Ad-5, El-deleted) carrying a proapoptotic human Fas-chimera transgene (Fas and human TNF receptor 1) under the control of a modified murine pre-proendothelin promoter (PPE-I-3x). This modified murine promoter is able to specifically target the expression of the Fas-chimera transgene to angiogenic blood vessels, leading to targeted apoptosis of these vessels. Because the transgene specifically targets the endothelial cells on the luminal wall of the neovasculature, penetration through the blood brain barrier is not required.

We have recently published a phase I, open-label, multisite, sequenial dose-escalation clinical trial with a single dose of VB-111 showing that VB-111 is safe and well tolerated in patients with advanced metastatic cancer at a single infusion of up to 1E13 viral particles (VPs), with evidence of transgene expression in tumor tissue and tumor responses observed. In addition, a phase II open-label multicenter study is being condicted to determine the efficacy of VB-111 in treating patients with GBM. Here we confirm in two independent pre-clinical models of GBM that VB-111 significantly extends survival, inhibits tumor growth and decreases the volume of angiogenic vessels within the tumor. Given the data presented herein, coupled with human trials, we conclude that VB-111 displays efficacy as a new antiangiogenic agent for the treatment of glioblastoma.

http://link.springer.com/article/10.1007/s11060-015-1853-7