Enhanced Antitumor Efficacy of Vasculostatin (Vstat120) Expressing Oncolytic HSV-1

Hardcastle, Jayson; Kurozumi, Kazuhiko; Dmitrieva, Nina; Sayers, Martin P.; Ahmad, Sarwat; Waterman, Peter; Weissleder, Ralph; Chiocca, E. Antonio; Kaur, Balveen

doi:10.1038/mt.2009.232

Cited by 85 publications

(92 citation statements)

References 47 publications

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“…We also observed that oncolytic viral therapy with HF10 enhanced angiogenesis, possibly due to the inflammatory response induced by viral infection, and viral proteins expressed during viral replication. 30 The mechanisms underlying the enhanced inflammation are not precisely known, but preclinical data regarding herpetic stromal keratitis in wild-type HSV 1 infection revealed that angiogenesis may be induced by paracrine effects resulting from release of VP22 or the CpG motifs in the DNA of HSV 1, which are required for viral replication. [57][58][59][60] Most of these stimuli, especially the CpG motif, potently stimulate secretion of vascular endothelial growth factor (VEGF) A.…”

Section: X400 X400mentioning

confidence: 99%

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Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

et al. 2011

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Oncolytic viruses are a promising method of cancer therapy, even for advanced malignancies. HF10, a spontaneously mutated herpes simplex type 1, is a potent oncolytic agent. The interaction of oncolytic herpes viruses with the tumor microenvironment has not been well characterized. We injected HF10 into tumors of patients with recurrent breast carcinoma, and sought to determine its effects on the tumor microenvironment. Six patients with recurrent breast cancer were recruited to the study. Tumors were divided into two groups: saline-injected (control) and HF10-injected (treatment). We investigated several parameters including neovascularization (CD31) and tumor lymphocyte infiltration (CD8, CD4), determined by immunohistochemistry, and apoptosis, determined by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Median apoptotic cell count was lower in the treatment group (P ¼ 0.016). Angiogenesis was significantly higher in treatment group (P ¼ 0.032). Count of CD8-positive lymphocytes infiltrating the tumors was higher in the treatment group (P ¼ 0.008). We were unable to determine CD4-positive lymphocyte infiltration. An effective oncolytic viral agent must replicate efficiently in tumor cells, leading to higher viral counts, in order to aid viral penetration. HF10 seems to meet this criterion; furthermore, it induces potent antitumor immunity. The increase in angiogenesis may be due to either viral replication or the inflammatory response.

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Section: X400 X400mentioning

confidence: 99%

“…[27][28][29] There are many attempts to engineer viruses to express antiangiogenic molecules. [30][31][32] Also obscuring the true effect of oncolytic herpes viruses on angiogenesis is the fact that all data have been generated in animal models rather than clinical investigation.…”

Section: Introductionmentioning

confidence: 99%

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

et al. 2011

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“…Human BAI1 expression is down-regulated in glioblastoma and is inversely correlated with neovascularization in colorectal and lung cancers, consistent with an antiangiogenesis function (20)(21)(22). The antiangiogenic activity of BAI1 is thought to be mediated by a fragment of its N-terminal extracellular sequence, a fragment known as vasculostatin (17,23,24). BAI2 and BAI3 expression are not p53-inducible, but both proteins also act as inhibitors of angiogenesis (11,14,15,25).…”

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confidence: 94%

The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins

Bolliger¹,

Martinelli²,

Südhof

2011

Proc. Natl. Acad. Sci. U.S.A.

154

162

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C1q-like genes (C1ql1-C1ql4) encode small, secreted proteins that are expressed in differential patterns in the brain but whose receptors and functions remain unknown. BAI3 protein, in contrast, is a member of the cell-adhesion class of G protein-coupled receptors that are expressed at high levels in the brain but whose ligands have thus far escaped identification. Using a biochemical approach, we show that all four C1ql proteins bind to the extracellular thrombospondin-repeat domain of BAI3 with high affinity, and that this binding is mediated by the globular C1q domains of the C1ql proteins. Moreover, we demonstrate that addition of submicromolar concentrations of C1ql proteins to cultured neurons causes a significant decrease in synapse density, and that this decrease was prevented by simultaneous addition of the thrombospondin-repeat fragment of BAI3, which binds to C1ql proteins. Our data suggest that C1ql proteins are secreted signaling molecules that bind to BAI3 and act, at least in part, to regulate synapse formation and/or maintenance.

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“…163 Combining a lower dose of G47Δ-mAngio with a low (non-invasive) dose of bevacizumab further improved survival. 163 Expression of other naturally occurring angiogenesis inhibitors, vasculostatin and CXCL4 (PF4), have also been shown to improve the efficacy of oHSV in human glioma models 164,165 (Table III). IL-12, in addition to its immunostimulatory activity is also antiangiogenic in GSC-derived gliomas (Cheema T, Rabkin SD; unpublished results).…”

Section: Disrupting Tumor Microenvironmentmentioning

confidence: 99%

“…U87 [163] HSVQ-Vstat120 HSV Vstat120 Nude, i.c. U87DEGFR [164] G47Δ-PF4 HSV PF4 (CXCL4) Nude, s.c. U87 [165] Ad-isthmin RD-Ad Xenopus isthmin Nude, i.c. U251 [166] CRAdRGDflt-IL24 Ad mda7/IL-24 Nude i.c.…”

mentioning

confidence: 99%

Current Status of Gene Therapy for Brain Tumors∗

Ning

Rabkin

2015

Translating Gene Therapy to the Clinic

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Glioblastoma (GBM) is the most common and deadliest primary brain tumor in adults, with current treatments having limited impact on disease progression. Therefore the development of alternative treatment options is greatly needed. Gene therapy is a treatment strategy that relies on the delivery of genetic material, usually transgenes or viruses, into cells for therapeutic purposes, and has been applied to GBM with increasing promise. We have included selectively replicationcompetent oncolytic viruses within this strategy, although the virus acts directly as a complex biologic anti-tumor agent rather than as a classic gene delivery vehicle. GBM is a good candidate for gene therapy because tumors remain locally within the brain and only rarely metastasize to other tissues; the majority of cells in the brain are post-mitotic, which allows for specific targeting of dividing tumor cells; and tumors can often be accessed neurosurgically for administration of therapy. Delivery vehicles used for brain tumors include nonreplicating viral vectors, normal adult stem/progenitor cells, and oncolytic viruses. The therapeutic transgenes or viruses are typically cytotoxic or express prodrug activating suicide genes to kill glioma cells, immunostimulatory to induce or amplify anti-tumor immune responses, and/or modify the tumor microenvironment such as blocking angiogenesis. This review describes current preclinical and clinical gene therapy strategies for the treatment of glioma.Treating malignant gliomas, of which glioblastoma (GBM) is the most common and least curable, remains a daunting challenge even after substantial efforts to develop alternative therapies. The current standard of care is maximal surgical resection followed by radiation and temozolomide chemotherapy; however, the median survival still remains less than 15 months. 1,2 This poor survival is due to the aggressive and invasive nature of the tumor cells, resistance to treatment, and the challenges of delivering therapeutics into the brain. 3 GBM is thought to be derived from a small population of glioblastoma stem cells (GSCs), so-called because of their stem cell-like properties of self-renewal and multilineage differentiation while being highly tumorigenic. [4][5][6] GSCs have become an important model for studying GBM because their xenografts mimic the heterogeneous histopathology of the patient's tumor from which they were derived 7,8 and they remain genotypically similar to the patient's tumor, in contrast to serum-cultured cell lines. 9 These cells have provided insights into the origin of tumor-initiating cells and new targets for therapy. Other GBM animal models include established glioma cell lines (human and rodent) implanted intracranially into immunodeficient or immunocompetent animals, and genetically engineered mice that spontaneously develop brain tumors or are induced with viral vectors. 10 GENE DELIVERY VEHICLES FOR GLIOBLASTOMAMost gene therapies for GBM use biologic vectors such as viruses or cells. Replicationdefective or non-repli...

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Enhanced Antitumor Efficacy of Vasculostatin (Vstat120) Expressing Oncolytic HSV-1

Cited by 85 publications

References 47 publications

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins

Current Status of Gene Therapy for Brain Tumors∗

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