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VB-111: a novel anti-vascular therapeutic for glioblastoma multiforme

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Abstract

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.

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Authors and Affiliations

  1. Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229-3900, USA

    Aleksandra Gruslova, David A. Cavazos, Jessica R. Miller, Anu Soundararajan, John R. Floyd & Andrew J. Brenner

  2. VBL Therapeutics, 6 Jonathan Netanyahu St., Or Yehuda, 60376, Israel

    Eyal Breitbart, Yael C. Cohen, Livnat Bangio & Niva Yakov

Authors
  1. Aleksandra Gruslova
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  2. David A. Cavazos
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  3. Jessica R. Miller
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  4. Eyal Breitbart
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  5. Yael C. Cohen
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  6. Livnat Bangio
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  7. Niva Yakov
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  8. Anu Soundararajan
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  9. John R. Floyd
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  10. Andrew J. Brenner
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Corresponding author

Correspondence to Andrew J. Brenner.

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Conflict of interest

A. B. received a commercial research Grant from and is a consultant/advisory board member of Vascular Biogenics. Y.C.C., L.B., N. Y. and E. B. are employed by and have ownership interest in VBL Therapeutics.

Funding

The study was supported by in part by the UTHSCSA Cancer Therapy and Research Center through the National Institutes of Health National Cancer Institute P30 award CA054174, as well as by a service agreement with VBL Therapeutics.

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Gruslova, A., Cavazos, D.A., Miller, J.R. et al. VB-111: a novel anti-vascular therapeutic for glioblastoma multiforme. J Neurooncol 124, 365–372 (2015). https://doi.org/10.1007/s11060-015-1853-7

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  • DOI: https://doi.org/10.1007/s11060-015-1853-7

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