Targeting tumor vasculature with an oncolytic virus

Centre for Cancer Therapeutics, Ottawa Health Research Institute, Ottawa, Ontario, Canada.
Molecular Therapy (Impact Factor: 6.43). 03/2011; 19(5):886-94. DOI: 10.1038/mt.2011.26
Source: PubMed

ABSTRACT Oncolytic viruses (OVs) have been engineered or selected for cancer cell-specific infection however, we have found that following intravenous administration of vesicular stomatitis virus (VSV), tumor cell killing rapidly extends far beyond the initial sites of infection. We show here for the first time that VSV directly infects and destroys tumor vasculature in vivo but leaves normal vasculature intact. Three-dimensional (3D) reconstruction of infected tumors revealed that the majority of the tumor mass lacks significant blood flow in contrast to uninfected tumors, which exhibit relatively uniform perfusion. VSV replication in tumor neovasculature and spread within the tumor mass, initiates an inflammatory reaction including a neutrophil-dependent initiation of microclots within tumor blood vessels. Within 6 hours of intravenous administration of VSV and continuing for at least 24 hours, we observed the initiation of blood clots within the tumor vasculature whereas normal vasculature remained clot free. Blocking blood clot formation with thrombin inhibitors prevented tumor vascular collapse. Our results demonstrate that the therapeutic activity of an OV can go far beyond simple infection and lysis of malignant cells.

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    • "Finally, VSV oncotoxicity can be improved by targeting tumour vasculature. A recent study has shown the ability of VSV to target tumour vasculature and angiogenesis when administered subcutaneously to mice with colon adenocarcinoma (Breitbach et al., 2011). The use of antiangiogenic vascular endothelial growth factor 165 inhibitor combined with VSV led to increased tumour regression and improved virus titre and dissemination, even within tumours that previously supported poor VSV replication (Kottke et al., 2010). "
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    ABSTRACT: Oncolytic virus (OV) therapy is an emerging anti-cancer approach that utilizes viruses to preferentially infect and kill cancer cells, while not harming healthy cells. Vesicular stomatitis virus (VSV) is a prototypic non-segmented, negative-strand RNA virus with inherent OV qualities. Antiviral responses induced by type I interferon pathways are believed to be impaired in most cancer cells, making them more susceptible to VSV than normal cells. Several other factors make VSV a promising OV candidate for clinical use, including its well-studied biology, a small, easily manipulated genome, relative independence of a receptor or cell cycle, cytoplasmic replication without risk of host-cell transformation, and lack of pre-existing immunity in humans. Moreover, various VSV-based recombinant viruses have been engineered via reverse genetics to improve oncoselectivity, safety, oncotoxicity and stimulation of tumour-specific immunity. Alternative delivery methods are also being studied to minimize premature immune clearance of VSV. OV treatment as a monotherapy is being explored, although many studies have employed VSV in combination with radiotherapy, chemotherapy or other OVs. Preclinical studies with various cancers have demonstrated that VSV is a promising OV; as a result, a human clinical trial using VSV is currently in progress.
    Journal of General Virology 10/2012; 93(Pt_12). DOI:10.1099/vir.0.046672-0 · 3.53 Impact Factor
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    • "Thus, an effective targeting of multiple components by the combination treatment could explain its efficacy not only in the treatment of the primary tumour, but most importantly, against spontaneous metastasis. The latter effect could be associated with vascular shutdown in the primary tumours that affected migration of the metastatic cells to other organs after a neutrophil-dependent initiation of microclots within tumour blood vessels (Breitbach et al, 2011). Our observation of vascular collapse and infiltration of neutrophils/ MDSCs after treatment with OVV-EGFP is consistent with previous studies in a murine model using VSV (Breitbach et al, 2007). "
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    ABSTRACT: Therapies targeted towards the tumour vasculature can be exploited for the purpose of improving the systemic delivery of oncolytic viruses to tumours. Photodynamic therapy (PDT) is a clinically approved treatment for cancer that is known to induce potent effects on tumour vasculature. In this study, we examined the activity of PDT in combination with oncolytic vaccinia virus (OVV) against primary and metastatic tumours in mice. The effect of 2-[1-hexyloxyethyl-]-2-devinyl pyropheophorbide-a (HPPH)-sensitised-PDT on the efficacy of oncolytic virotherapy was investigated against subcutaneously implanted syngeneic murine NXS2 neuroblastoma and human FaDu head and neck squamous cell carcinoma xenografts in nude mice. Treatment efficacy was evaluated by monitoring tumour growth and survival. The effects of combination treatment on vascular function were examined using magnetic resonance imaging (MRI) and immunohistochemistry, whereas viral replication in tumour cells was analysed by a standard plaque assay. Normal tissue phototoxicity following PDT-OV treatment was studied using the mouse foot response assay. Combination of PDT with OVV resulted in inhibition of primary and metastatic tumour growth compared with either monotherapy. PDT-induced vascular disruption resulted in higher intratumoural viral titres compared with the untreated tumours. Five days after delivery of OVV, there was a loss of blood flow to the interior of tumour that was associated with infiltration of neutrophils. Administration of OVV did not result in any additional photodynamic damage to normal mouse foot tissue. These results provide evidence into the usefulness of PDT as a means of enhancing intratumoural replication and therapeutic efficacy of OV.
    British Journal of Cancer 11/2011; 105(10):1512-21. DOI:10.1038/bjc.2011.429 · 4.82 Impact Factor
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    ABSTRACT: The efficient delivery of viral vectors to tumors is an active area of investigation. A number of barriers exist that must be overcome to achieve good penetration of vectors into tumors and distribution of their effects throughout the tumor mass. Replicating oncolytic viruses have the advantage of being able to amplify the initial dose, but progeny virus are prevented from spreading because of a dense mass of tightly packed cells with a dense extracellular matrix, admixed normal stromal cells, and high interstitial pressure. Although intratumoral injection may ensure initial delivery the distribution achieved by intravenous administration may be superior and come with beneficial bystander damage to the tumor vasculature. Strategies to enhance intravenous delivery and subsequent spread of these vectors within tumors are being developed by a number of groups. Achieving the goal of efficient penetration and spread of viruses within solid tumors is a necessary prerequisite to significant improvements in virus-vectored therapy of solid tumors.
    Human gene therapy 03/2011; 22(9):1053-60. DOI:10.1089/hum.2010.227 · 3.62 Impact Factor
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