Goel, A, Carlson, SK, Classic, KL, Greiner, S, Naik, S, Power, AT et al.. Radioiodide imaging and radiovirotherapy of multiple myeloma using VSV(Delta51)-NIS, an attenuated vesicular stomatitis virus encoding the sodium iodide symporter gene. Blood 110: 2342-2350

University of Ottawa, Ottawa, Ontario, Canada
Blood (Impact Factor: 10.45). 11/2007; 110(7):2342-50. DOI: 10.1182/blood-2007-01-065573
Source: PubMed


Multiple myeloma is a radiosensitive malignancy that is currently incurable. Here, we generated a novel recombinant vesicular stomatitis virus [VSV(Delta51)-NIS] that has a deletion of methionine 51 in the matrix protein and expresses the human sodium iodide symporter (NIS) gene. VSV(Delta51)-NIS showed specific oncolytic activity against myeloma cell lines and primary myeloma cells and was able to replicate to high titers in myeloma cells in vitro. Iodide uptake assays showed accumulation of radioactive iodide in VSV(Delta51)-NIS-infected myeloma cells that was specific to the function of the NIS transgene. In bg/nd/xid mice with established subcutaneous myeloma tumors, administration of VSV(Delta51)-NIS resulted in high intratumoral virus replication and tumor regression. VSV-associated neurotoxicity was not observed. Intratumoral spread of the infection was monitored noninvasively by serial gamma camera imaging of (123)I-iodide biodistribution. Dosimetry calculations based on these images pointed to the feasibility of combination radiovirotherapy with VSV(Delta51)-NIS plus (131)I. Immunocompetent mice with syngeneic 5TGM1 myeloma tumors (either subcutaneous or orthotopic) showed significant enhancements of tumor regression and survival when VSV(Delta51)-NIS was combined with (131)I. These results show that VSV(Delta51)-NIS is a safe oncolytic agent with significant therapeutic potential in multiple myeloma.

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    • "This group also found that a deletion of methionine 51 (VSVΔM51) similarly reduced neurotoxicity, and later studies using this neuroattenuated virus have shown that it can safely and effectively treat mice with multifocal and invasive gliomas, subcutaneous myeloma tumors, and metastatic breast cancer.24, 25, 38, 39 Similarly, attenuated neurotoxicity has also been demonstrated when the IFN-β gene is directly engineered into the genome of VSV (VSV-IFNβ). Intravenous injection of VSV-IFNβ into BALB/c mice, for example, determined that this virus was 50 times more attenuated than wild-type VSV, due to IFN-β expression.27 "
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    ABSTRACT: Vesicular stomatitis virus (VSV) is neuropathogenic in rodents but can be attenuated 50-fold by engineering the mouse interferon-beta (IFN-β) gene into its genome. Intravenously administered VSVs encoding IFN-β have potent activity against subcutaneous tumors in the 5TGM1 mouse myeloma model, without attendant neurotoxicity. However, when 5TGM1 tumor cells were seeded intravenously, virus-treated mice with advanced myeloma developed clinical signs suggestive of meningoencephalitis. Co-administration of a known active antimyeloma agent did not prolong survival, further suggesting that deaths were due to viral toxicity, not tumor burden. Histological analysis revealed that systemically administered 5TGM1 cells seed to the CNS, forming meningeal tumor deposits, and that VSV infects and destroys these tumors. Death is presumably a consequence of meningeal damage and/or direct transmission of virus to adjacent neural tissue. In light of these studies, extreme caution is warranted in clinical testing of attenuated VSVs, particularly in patients with CNS tumor deposits.Cancer Gene Therapy advance online publication, 1 November 2013; doi:10.1038/cgt.2013.63.
    Cancer gene therapy 11/2013; 20(11). DOI:10.1038/cgt.2013.63 · 2.42 Impact Factor
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    • "Recombinant VSV-GFP virus was amplified in Vero cells as previously described25. Viruses were purified by 0.45 μm filtration of cell supernatant and pelleted by ultra-centrifugation (27,000 rpm) through a 10% w/v sucrose gradient. "
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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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    • "Imaging of VSV-GFP or VSV-luciferase is widely used in rodent models, but requires levels of expression that may not be attainable in human clinical studies. Whilst VSV-NIS in combination with iodine-123 allows sensitive monitoring of infection, it is mostly applicable to studies involving radioisotopes (Goel et al., 2007; Naik et al., 2012). "
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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 · 3.18 Impact Factor
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