Targeting Tumor Vasculature With an Oncolytic Virus

Centre for Cancer Therapeutics, Ottawa Health Research Institute, Ottawa, Ontario, Canada.
Molecular Therapy (Impact Factor: 6.23). 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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    • "This approach may be particularly useful for treating apoptosis-resistant types of cancer, thus warranting further development toward clinical application. Lastly, some OVs can exert indirect mechanisms of tumor killing, including tumor vascular shutdown (40, 41) and the induction of antitumor immune responses, the latter of which is described in further detail in the following section. "
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    ABSTRACT: Cancer is a traitorous archenemy that threatens our survival. Its ability to evade detection and adapt to various cancer therapies means that it is a moving target that becomes increasingly difficult to attack. Through technological advancements, we have developed sophisticated weapons to fight off tumor growth and invasion. However, if we are to stand a chance in this war against cancer, advanced tactics will be required to maximize the use of our available resources. Oncolytic viruses (OVs) are multi-functional cancer-fighters that can be engineered to suit many different strategies; in particular, their retooling can facilitate increased capacity for direct tumor killing (oncolytic virotherapy) and elicit adaptive antitumor immune responses (oncolytic immunotherapy). However, administration of these modified OVs alone, rarely induces successful regression of established tumors. This may be attributed to host antiviral immunity that acts to eliminate viral particles, as well as the capacity for tumors to adapt to therapeutic selective pressure. It has been shown that various chemotherapeutic drugs with distinct functional properties can potentiate the antitumor efficacy of OVs. In this review, we summarize the chemotherapeutic combinatorial strategies used to optimize virally induced destruction of tumors. With a particular focus on pharmaceutical immunomodulators, we discuss how specific therapeutic contexts may alter the effects of these synergistic combinations and their implications for future clinical use.
    Frontiers in Oncology 06/2014; 4:145. DOI:10.3389/fonc.2014.00145
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    • "However, some OVs display an innate ability to infect ECs in tumors, while sparing those in normal vessels [39]. This induced neutrophil infiltration, leading to microclot formation within the tumor-associated vasculature, resulting in a large bystander effect of cell death within the tumor [40]. This provides a useful platform for the further development of OVs armed with therapeutic transgenes in the future. "
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    ABSTRACT: Viruses have demonstrated strong potential for the therapeutic targeting of glioblastoma stem cells (GSCs). In this study, the use of a herpes simplex virus carrying endostatin-angiostatin (VAE) as a novel therapeutic targeting strategy for glioblastoma-derived cancer stem cells was investigated. We isolated six stable GSC-enriched cultures from 36 human glioblastoma specimens and selected one of the stable GSCs lines for establishing GSC-carrying orthotopic nude mouse models. The following results were obtained: (a) VAE rapidly proliferated in GSCs and expressed endo-angio in vitro and in vivo 48 h and 10 d after infection, respectively; (b) compared with the control gliomas treated with rHSV or Endostar, the subcutaneous gliomas derived from the GSCs showed a significant reduction in microvessel density after VAE treatment; (c) compared with the control, a significant improvement was observed in the length of the survival of mice with intracranial and subcutaneous gliomas treated with VAE; (d) MRI analysis showed that the tumor volumes of the intracranial gliomas generated by GSCs remarkably decreased after 10 d of VAE treatment compared with the controls. In conclusion, VAE demonstrated oncolytic therapeutic efficacy in animal models of human GSCs and expressed an endostatin-angiostatin fusion gene, which enhanced antitumor efficacy most likely by restricting tumor microvasculature development.
    PLoS ONE 04/2014; 9(4):e95872. DOI:10.1371/journal.pone.0095872 · 3.23 Impact Factor
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    • "Pre-conditioning of host with cyclophosphamide before virus administration can help to increase overall viral titer in tumors as well as suppress induction of primary antiviral antibodies and the anamnestic response161718. Viral spread can also be shut down due to destruction of vascular structures by VSV replication within the tumor mass, initiating an inflammatory reaction including a neutrophil-dependent initiation of microclots within tumor blood vessels19. Physical barriers imposed by tumor architecture can hinder progeny spread to other tumor nests within the stroma20. Suboptimal vascular perfusion in poorly vascularized tumors also reduces virus delivery and therapeutic outcome. "
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    ABSTRACT: Oncolytic viruses obliterate tumor cells in tissue culture but not against the same tumors in vivo. We report that macrophages can induce a powerfully protective antiviral state in ovarian and breast tumors, rendering them resistant to oncolytic virotherapy. These tumors have activated JAK/STAT pathways and expression of interferon-stimulated genes (ISGs) is upregulated. Gene expression profiling (GEP) of human primary ovarian and breast tumors confirmed constitutive activation of ISGs. The tumors were heavily infiltrated with CD68+ macrophages. Exposure of OV-susceptible tumor cell lines to conditioned media from RAW264.7 or primary macrophages activated antiviral ISGs, JAK/STAT signaling and an antiviral state. Anti-IFN antibodies and shRNA knockdown studies show that this effect is mediated by an extremely low concentration of macrophage-derived IFNβ. JAK inhibitors reversed the macrophage-induced antiviral state. This study points to a new role for tumor-associated macrophages in the induction of a constitutive antiviral state that shields tumors from viral attack.
    Scientific Reports 08/2013; 3:2375. DOI:10.1038/srep02375 · 5.58 Impact Factor
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