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
ABSTRACT 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.
- SourceAvailable from: Eric Hastie
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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). "
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
Modern Practices in Radiation Therapy, 03/2012; , ISBN: 978-953-51-0427-8
- "Oncolytic viruses have been used for radiotargeted gene therapy whereby radionuclides can be localized at tumor sites by inducing tumor cells to express sodium-iodide symporter (hNIS) gene (radiovirotherapy) (Chung, 2002). Such " designer oncolytic viruses " that express the human NIS gene have been engineered and tested in MM (Dingli et al., 2004; Goel et al., 2007). By using radionuclides, such as iodine-123, iodine-124, or technicium- 99m, combined with detection with either a γ camera, positron emission tomography (PET), or single photon emission computed tomography (SPECT)/computed tomography (CT), NIS can be used as a reporter gene to non-invasively monitor viral localization and spread. "
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- "This treatment cycle was repeated once on days 7 and 8. 131 I therapy after systemic G2-HD- OEI/NIS application resulted in a significant delay in tumor growth (A, *p < 0.05), which was associated with markedly improved survival (B, Kaplan–Meier plot) as compared with the control groups that were injected with saline only, with G2-HD-OEI/ NIS followed by saline application, or with G2-HD-OEI/antisense-NIS followed by saline or 131 I. setting of metastatic cancer concerns optimal tumor targeting in the presence of low toxicity and sufficiently high transduction efficiency after systemic administration of gene delivery vectors. Only a limited number of studies have investigated systemic NIS gene delivery approaches with the aim of NIS-targeted radionuclide therapy of metastatic disease (Dingli et al., 2004; Goel et al., 2007; Klutz et al., 2009; Liu et al., 2010). "
ABSTRACT: We reported the induction of tumor-selective iodide uptake and therapeutic efficacy of (131)I in a hepatocellular carcinoma (HCC) xenograft mouse model, using novel polyplexes based on linear polyethylenimine (LPEI), shielded by polyethylene glycol (PEG), and coupled with the epidermal growth factor receptor-specific peptide GE11 (LPEI-PEG-GE11). The aim of the current study in the same HCC model was to evaluate the potential of biodegradable nanoparticle vectors based on pseudodendritic oligoamines (G2-HD-OEI) for systemic sodium iodide symporter (NIS) gene delivery and to compare efficiency and tumor specificity with LPEI-PEG-GE11. Transfection of HCC cells with NIS cDNA, using G2-HD-OEI, resulted in a 44-fold increase in iodide uptake in vitro as compared with a 22-fold increase using LPEI-PEG-GE11. After intravenous application of G2-HD-OEI/NIS HCC tumors accumulated 6-11% ID/g (123)I (percentage of the injected dose per gram tumor tissue) with an effective half-life of 10 hr (tumor-absorbed dose, 281 mGy/MBq) as measured by (123)I scintigraphic gamma camera or single-photon emission computed tomography computed tomography (SPECT CT) imaging, as compared with 6.5-9% ID/g with an effective half-life of only 6 hr (tumor-absorbed dose, 47 mGy/MBq) for LPEI-PEG-GE11. After only two cycles of G2-HD-OEI/NIS/(131)I application, a significant delay in tumor growth was observed with markedly improved survival. A similar degree of therapeutic efficacy had been observed after four cycles of LPEI-PEG-GE11/(131)I. These results clearly demonstrate that biodegradable nanoparticles based on OEI-grafted oligoamines show increased efficiency for systemic NIS gene transfer in an HCC model with similar tumor selectivity as compared with LPEI-PEG-GE11, and therefore represent a promising strategy for NIS-mediated radioiodine therapy of HCC.Human gene therapy 08/2011; 22(12):1563-74. DOI:10.1089/hum.2011.041 · 3.62 Impact Factor