A Novel Recombinant Vaccinia Virus Expressing the Human Norepinephrine Transporter Retains Oncolytic Potential and Facilitates Deep-Tissue Imaging

Chen, Nanhai; Zhang, Qian; Yu, Yong A.; Stritzker, Jochen; Brader, Peter; Schirbel, Andreas; Samnick, Samuel; Serganova, Inna; Blasberg, Ronald G.; Fong, Yuman; Szalay, Aladar A.

doi:10.2119/molmed.2009.00014

Cited by 37 publications

(33 citation statements)

References 24 publications

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“…In addition, we showed functionality of second-generation recombinant vaccinia viruses armed with the human norepinephrine transporter [24] and the human sodium iodide symporter gene [25] for PET imaging, or single-chain antibody GLAF-1 targeting VEGF and tumor vascularization in vivo [26]. We also demonstrated preferential replication in glioblastoma cells and higher efficacy in treating gliomas in combination with radiation therapy [27].…”

Section: Introductionmentioning

confidence: 99%

Growth inhibition of different human colorectal cancer xenografts after a single intravenous injection of oncolytic vaccinia virus GLV-1h68

et al. 2013

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BackgroundDespite availability of efficient treatment regimens for early stage colorectal cancer, treatment regimens for late stage colorectal cancer are generally not effective and thus need improvement. Oncolytic virotherapy using replication-competent vaccinia virus (VACV) strains is a promising new strategy for therapy of a variety of human cancers.MethodsOncolytic efficacy of replication-competent vaccinia virus GLV-1h68 was analyzed in both, cell cultures and subcutaneous xenograft tumor models.ResultsIn this study we demonstrated for the first time that the replication-competent recombinant VACV GLV-1h68 efficiently infected, replicated in, and subsequently lysed various human colorectal cancer lines (Colo 205, HCT-15, HCT-116, HT-29, and SW-620) derived from patients at all four stages of disease. Additionally, in tumor xenograft models in athymic nude mice, a single injection of intravenously administered GLV-1h68 significantly inhibited tumor growth of two different human colorectal cell line tumors (Duke’s type A-stage HCT-116 and Duke’s type C-stage SW-620), significantly improving survival compared to untreated mice. Expression of the viral marker gene ruc-gfp allowed for real-time analysis of the virus infection in cell cultures and in mice. GLV-1h68 treatment was well-tolerated in all animals and viral replication was confined to the tumor. GLV-1h68 treatment elicited a significant up-regulation of murine immune-related antigens like IFN-γ, IP-10, MCP-1, MCP-3, MCP-5, RANTES and TNF-γ and a greater infiltration of macrophages and NK cells in tumors as compared to untreated controls.ConclusionThe anti-tumor activity observed against colorectal cancer cells in these studies was a result of direct viral oncolysis by GLV-1h68 and inflammation-mediated innate immune responses. The therapeutic effects occurred in tumors regardless of the stage of disease from which the cells were derived. Thus, the recombinant vaccinia virus GLV-1h68 has the potential to treat colorectal cancers independently of the stage of progression.

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Section: Introductionmentioning

confidence: 99%

Growth inhibition of different human colorectal cancer xenografts after a single intravenous injection of oncolytic vaccinia virus GLV-1h68

et al. 2013

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“…GLV-1h164 was generated from GLV-1h100 using pHA-PSL-GLAF-2. All recombinant viruses were constructed using the method described previously [13]. The genotype of each recombinant virus was confirmed by PCR and sequencing.…”

Section: Methodsmentioning

confidence: 99%

A novel vaccinia virus with dual oncolytic and anti-angiogenic therapeutic effects against triple-negative breast cancer

Gholami

Marano

Chen

et al. 2014

Breast Cancer Res Treat

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Purpose Vascular endothelial growth factor (VEGF) expression is higher in triple-negative breast cancers (TNBC) compared to other subtypes and is reported to predict incidence of distant metastases and shorter overall survival. We investigated the therapeutic impact of a vaccinia virus (VACV) GLV-1h164 (derived from its parent virus GLV-1h100), encoding a single-chain antibody (scAb) against VEGF (GLAF-2) in an orthotopic TNBC murine model. Methods GLV-1h164 was tested against multiple TNBC cell lines. Viral infectivity, cytotoxicity, and replication were determined. Mammary fat pad tumors were generated in athymic nude mice using MDA-MB-231 cells. Xenografts were treated with GLV-1h164, GLV-1h100, or PBS and followed for tumor growth. Results Viral infectivity was time- and concentration-dependent. GLV-1h164 killed TNBC cell lines in a dose-dependent fashion with greater than 90% cytotoxicity within 4 days at a multiplicity of infection of 5.0. In vitro, cytotoxicity of GLV-1h164 was identical to GLV-1h100. GLV-1h164 replicated efficiently in all cell lines with an over 400-fold increase in copy numbers from the initial viral dose within 4 days. In vivo, mean tumor volumes after 2 weeks of treatment were 73, 191, and 422mm3 (GLV-1h164, GLV-1h100, and PBS, respectively) (p<0.05). Both in vivo Doppler ultrasonography and immuno-staining showed decreased neo-angiogenesis in GLV-1h164-treated tumors compared to both GLV-1h100 and PBS controls (p<0.05). Conclusion This is the first study to demonstrate efficient combination of oncolytic and anti-angiogenic activity of a novel vaccinia virus on TNBC xenografts. Our results suggest that GLV-1h164 is a promising therapeutic agent that warrants testing for patients with TNBC.

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“…The TurboFP635 cDNA was then released from pCRII-FUKW with Sal I and Pac I , and subcloned into TK-SEL-hNISa8 with the same cuts, replacing the hNIS cDNA. The resulting sequence confirmed construct TK-SEL-FUKW1 was used to make recombinant virus GLV-2b372 using LIVP 1.1.1 as the parental virus as described previously (8). …”

Section: Methodsmentioning

confidence: 99%

Oncolytic gene therapy with recombinant vaccinia strain GLV-2b372 efficiently kills hepatocellular carcinoma

Ady¹,

Johnsen²,

Mojica³

et al. 2015

Surgery

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Background Hepatocellular carcinoma (HCC) commonly presents at a late stage when surgery is no longer a curative option. As such, novel therapies for advanced HCC are needed. Oncolytic viruses are a viable option for cancer therapy due to their ability to specifically infect, replicate within, and kill cancer cells. In this study we investigate the ability of GLV-2b372, a novel light-emitting recombinant vaccinia virus derived from a wild-type Lister strain, to kill HCC. Methods Four human HCC cell lines were assayed in vitro for infectivity and cytotoxicity. Viral replication was quantified via standard viral plaque assays. Flank HCC xenografts generated in athymic nude mice were treated with intratumoral GLV-2b372 to assess for tumor growth inhibition and viral biodistribution. Results Infectivity occurred in a time and concentration dependent manner with 70% cell death in all cell lines by day 5. All cell lines supported efficient viral replication. At 25 days post infection, flank tumor volumes decreased by 50% while controls increased by 400%. Tumor tissue demonstrated substantial GLV-2b372 infection at 24 hours, 48 hours and at 2 weeks. Conclusions We demonstrate that GLV-2b372 efficiently kills human HCC in vitro and in vivo and is a viable treatment option for patients with HCC.

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A Novel Recombinant Vaccinia Virus Expressing the Human Norepinephrine Transporter Retains Oncolytic Potential and Facilitates Deep-Tissue Imaging

Cited by 37 publications

References 24 publications

Growth inhibition of different human colorectal cancer xenografts after a single intravenous injection of oncolytic vaccinia virus GLV-1h68

Growth inhibition of different human colorectal cancer xenografts after a single intravenous injection of oncolytic vaccinia virus GLV-1h68

A novel vaccinia virus with dual oncolytic and anti-angiogenic therapeutic effects against triple-negative breast cancer

Oncolytic gene therapy with recombinant vaccinia strain GLV-2b372 efficiently kills hepatocellular carcinoma

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