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Or Yehuda, Israel

Gruslova A.,University of Texas Health Science Center at San Antonio | Cavazos D.A.,University of Texas Health Science Center at San Antonio | Miller J.R.,University of Texas Health Science Center at San Antonio | Breitbart E.,VBL Therapeutics | And 6 more authors.
Journal of Neuro-Oncology | Year: 2015

Glioblastoma multiforme (GBM) is among the most highly vascularized of solid tumors, contributing to the infiltrative nature of the disease, and conferring poor outcome. Due to the critical dependency of GBM on growth of new endothelial vasculature, we evaluated the preclinical activity of a novel adenoviral gene therapy that targets the endothelium within newly formed blood vessels for apoptosis. VB-111, currently in phase II clinical trials, consists of a non-replicating Adenovirus 5 (El deleted) carrying a proapoptotic human Fas-chimera (transgene) under the control of a modified murine promoter (PPE-1-3×) which specifically targets endothelial cells within the tumor vasculature. Here we report that a single intravenous dose of 2.5 × 1011 or 1 × 1011 VPs was sufficient to extend survival in nude rats bearing U87MG-luc2 or nude mice bearing U251-luc, respectively. Bioluminescence imaging of nude rats showed that VB-111 effectively inhibited tumor growth within four weeks of treatment. This was confirmed in a select group of animals by MRI. In our mouse model we observed that 3 of 10 nude mice treated with VB-111 completely lost U251 luciferase signal and were considered long term survivors. To assess the antiangiogenic effects of VB-111, we evaluated the tumor-associated microvaculature by CD31, a common marker of neovascularization, and found a significant decrease in the microvessel density by IHC. We further assessed the neovasculature by confocal microscopy and found that VB-111 inhibits vascular density in two separate mouse models bearing U251-RFP xenografts. Collectively, this study supports the clinical development of VB-111 as a treatment for GBM. © 2015, Springer Science+Business Media New York. Source

Brenner A.J.,University of Texas Health Science Center at San Antonio | Cohen Y.C.,VBL Therapeutics | Breitbart E.,VBL Therapeutics | Bangio L.,VBL Therapeutics | And 5 more authors.
Clinical Cancer Research | Year: 2013

Purpose: VB-111 is an antiangiogenic agent consisting of a nonreplicating adenovirus vector (Ad-5) with a modified murine pre-proendothelin promoter leading to apoptosis of tumor vasculature by expressing a Fas-chimera transgene in angiogenic endothelial cells. In a phase I dose-escalation study, pharmacokinetics, pharmacodynamics, safety, and efficacy of a single dose of VB-111 in patients with advanced solid tumors were evaluated. Experimental Design: VB-111 was administered as a single i.v. infusion at escalating doses from 1×1010 (cohort 1) to 1 × 1013 (cohort 7) viral particles (VP) in successive cohorts. Assessments included pharmacokinetic and pharmacodynamic profiles, tumor response, and overall survival. Results: Thirty-three patients were enrolled. VB-111 was safe and well-tolerated; self-limited fever and chills were seen at doses above 3 × 1011 VPs. Transgene expression was not detected in blood but was detected in an aspirate from a subcutaneous metastasis after treatment. One patient with papillary thyroid carcinoma had a partial response. Conclusions: VB-111 was safe and well tolerated in patients with advanced metastatic cancer at a single administration of up to 1 × 1013 VPs. Evidence of transgene expression in tumor tissue and tumor response was observed. © 2013 American Association for Cancer Research. Source

Reddi H.V.,Foundation Medicine | Madde P.,Foundation Medicine | Cohen Y.C.,VBL Therapeutics | Bangio L.,VBL Therapeutics | And 5 more authors.
Genes and Cancer | Year: 2011

VB-111 is an engineered antiangiogenic adenovirus that expresses Fas-c in angiogenic blood vessels and has previously been shown to have significant antitumor activity in vitro and in vivo in Lewis lung carcinoma, melanoma, and glioblastoma models. To evaluate the efficacy of VB-111 in thyroid cancer, we conducted in vivo xenograft nude mouse studies using multiple thyroid cancer-derived cell lines models. VB-111 treatment resulted in 26.6% (P = 0.0596), 34.4% (P = 0.0046), and 37.6% (P = 0.0249) inhibition of tumor growth in follicular, papillary and anaplastic thyroid cancer models, respectively. No toxicity was observed in any model. All tumor types showed a consistent and significant reduction of CD-31 staining (P < 0.05), reflecting a reduction of angiogenic activity in the tumors, consistent with the intended targeting of the virus. A phase 2 clinical trial of VB-111 in patients with advanced differentiated thyroid cancer is ongoing. © The Author(s) 2011. Source

Mendel I.,VBL Therapeutics | Yacov N.,VBL Therapeutics | Harats D.,VBL Therapeutics | Breitbart E.,VBL Therapeutics
Current Pharmaceutical Design | Year: 2015

Atherosclerosis is a smoldering disease of the vasculature that can lead to the occlusion of the arteries, resulting in ischemia of the heart and brain. For many years, the asserted underlying mechanism of atherosclerosis, supported by its epidemiology, was based on the “cholesterol hypothesis” that people with high blood cholesterol are at higher risk of developing cardiovascular disease. This hypothesis instigated a vigorous search for treatment that yielded the generation of statins, which specifically reduce LDL cholesterol. Since then, statins have revolutionized the way people are treated for the prevention of atherosclerosis. Nonetheless, despite this potent class of drugs, cardiovascular disease continues to be the leading cause of death in many parts of the world, suggesting that additional mechanisms are involved in disease pathogenesis. Intensive research has revealed that the atherosclerotic plaque is enriched with leukocytes, and that macrophages constitute the majority of immune cells in the lesion. Monocytes/macrophages are now recognized as the prime immune cells involved in the development of atherosclerosis and are implicated to affect the size, composition and vulnerability of the atherosclerotic plaque. While many of the macrophage-derived pro-inflammatory mechanisms associated with atherogenesis have been characterized, such as cell adhesion, cytokine production and protease secretion, there is a dearth of drugs that specifically target innate immunity for treating patients with atherosclerosis. This review presents pre-clinical studies, and in most cases following clinical trials with antagonists and agonists that have been designed to counteract inflammation in atherosclerosis and associated diseases, highlighting targets expressed predominantly in monocytes. © 2015 Bentham Science Publishers. Source

Mendel I.,VBL Therapeutics | Yacov N.,VBL Therapeutics | Shoham A.,VBL Therapeutics | Ishai E.,VBL Therapeutics | Breitbart E.,VBL Therapeutics
Digestive Diseases and Sciences | Year: 2016

Background and Aims: Previous studies demonstrated that toll-like receptors 4 and 2 (TLR-4 and TLR-2), which are expressed on liver-resident Kupffer, hepatic stellate cells, and circulating monocytes, play a role in nonalcoholic fatty liver disease. Lecinoxoids are oxidized phospholipids that antagonize TLR-2- and TLR-4-mediated activation of innate immune cells and inhibit monocyte migration. In this study, we tested the effect of two functionally different lecinoxoids on the development of nonalcoholic steatohepatitis and liver fibrosis in a mouse model. Methods: Two-day-old C57BL/6 mice were injected with streptozotocin and fed a high-fat diet from Week 4 after birth. At Week 6 post-birth, lecinoxoids VB-201 or VB-703 were given orally, once daily, for 3 weeks. Telmisartan was administered orally, once daily, for 3 weeks, as positive control. At experiment conclusion, biochemical indices were evaluated. HE stain and quantitative PCR were used to determine the extent of steatosis and steatohepatitis, and Sirius red stain was used to assess liver fibrosis. Results: Treatment with lecinoxoids did not alter the concentration of blood glucose, liver triglycerides, or steatosis compared with solvent-treated mice. However, whereas VB-201 inhibited the development of fibrosis and, to some extent, liver inflammation, VB-703 significantly lessened both liver inflammation and fibrosis. Conclusions: This study indicates that using lecinoxoids to antagonize TLR-2, and more prominently TLR-4, is sufficient to significantly inhibit nonalcoholic steatohepatitis and liver fibrosis. Inhibiting monocyte migration with lecinoxoids that are relatively weak TLR-4 antagonists may alter liver fibrosis and to some extent nonalcoholic steatohepatitis. © 2016 The Author(s) Source

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