Dataset Information

The integrin inhibitor cilengitide enhances the anti-glioma efficacy of vasculostatin-expressing oncolytic virus.

ABSTRACT: Oncolytic viral (OV) therapy has been considered as a promising treatment modality for brain tumors. Vasculostatin, the fragment of brain-specific angiogenesis inhibitor-1, shows anti-angiogenic activity against malignant gliomas. Previously, a vasculostatin-expressing oncolytic herpes simplex virus-1, Rapid Antiangiogenesis Mediated By Oncolytic virus (RAMBO), was reported to have a potent antitumor effect. Here, we investigated the therapeutic efficacy of RAMBO and cilengitide, an integrin inhibitor, combination therapy for malignant glioma. In vitro, tube formation was significantly decreased in RAMBO and cilengitide combination treatment compared with RAMBO or cilengitide monotherapy. Moreover, combination treatment induced a synergistic suppressive effect on endothelial cell migration compared with the control virus. RAMBO, combined with cilengitide, induced synergistic cytotoxicity on glioma cells. In the caspase-8 and -9 assays, the relative absorption of U87?EGFR cell clusters treated with cilengitide and with RAMBO was significantly higher than that of those treated with control. In addition, the activity of caspase 3/7 was significantly increased with combination therapy. In vivo, there was a significant increase in the survival of mice treated with combination therapy compared with RAMBO or cilengitide monotherapy. These results indicate that cilengitide enhanced vasculostatin-expressing OV therapy for malignant glioma and provide a rationale for designing future clinical trials combining these two agents.

SUBMITTER: Fujii K

PROVIDER: S-EPMC4862362 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The integrin inhibitor cilengitide enhances the anti-glioma efficacy of vasculostatin-expressing oncolytic virus.

Fujii K K Kurozumi K K Ichikawa T T Onishi M M Shimazu Y Y Ishida J J Chiocca E A EA Kaur B B Date I I

Cancer gene therapy 20130705 8

Oncolytic viral (OV) therapy has been considered as a promising treatment modality for brain tumors. Vasculostatin, the fragment of brain-specific angiogenesis inhibitor-1, shows anti-angiogenic activity against malignant gliomas. Previously, a vasculostatin-expressing oncolytic herpes simplex virus-1, Rapid Antiangiogenesis Mediated By Oncolytic virus (RAMBO), was reported to have a potent antitumor effect. Here, we investigated the therapeutic efficacy of RAMBO and cilengitide, an integrin inh ...[more]

PMID: 23827879

Similar Datasets

Project description:BACKGROUND:Monoclonal antibodies (mAbs) targeting negative regulators, or checkpoint molecules (e.g. PD1/PD-L1 & CTLA4), of anti-tumoural T cells have demonstrated clinical efficacy in treating several neoplastic diseases. While many patients enjoy remarkable responses to checkpoint inhibitors, a majority show adverse effects. Understanding how checkpoint inhibitors may augment established chemotherapy or radiotherapy regimens or other immunotherapies like oncolytic viruses may lead to better clinical outcomes measured by improved efficacy with reduced toxicity. Here, we assess how Newcastle disease virus (NDV), an oncolytic virus in clinical testing, may interact with radiotherapy to enhance checkpoint inhibitor blockade. METHODS:An immunocompetent B16-F10 murine melanoma model, generally considered to be a poorly immunogenic or "cold" tumour, was utilised to query whether combining localised radiotherapy with NDV may be more effective than either therapy alone in controlling tumours in mice treated with anti-PD1 or anti-CTLA4 monoclonal antibodies. We also investigated whether localised administration of a checkpoint inhibitor through an intratumoural injection of NDV that expresses anti-CTLA4 single-chain variable fragment (scFv) is comparable to systemic administration of anti-CTLA4 when combined with radiation in mediating its anti-tumour efficacy. Response rates were characterised by measuring tumour size over time, observation of complete tumour regression, and overall survival. FINDINGS:Our results show that combining NDV plus radiotherapy with checkpoint inhibitors (PD1 or CTLA4 targeted mAbs) results in significantly better complete tumour regression rates with an abscopal effect in a murine model of melanoma than either single therapy combined with checkpoint inhibitors. Finally, we also show that localised administration of a recombinant NDV expressing anti-CTLA4 plus radiation is comparable to systemic anti-CTLA4 plus radiation in mediating its anti-tumour effect as assayed by survival benefit. INTERPRETATION:Our results show that oncolytic NDV plus radiotherapy work together with checkpoint inhibitors to enhance tumour clearance of murine melanoma. NDV is an effective radiotherapy dose-sparing and immunotherapeutic agent capable of transgenic, in vivo expression of an anti-CTLA4 targeted scFv antibody with the potential to spare systemic exposure. FUNDING:The National Institutes of Health grant HHSN272201400008C supported the work. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Dataset Information

The integrin inhibitor cilengitide enhances the anti-glioma efficacy of vasculostatin-expressing oncolytic virus.

Publications

The integrin inhibitor cilengitide enhances the anti-glioma efficacy of vasculostatin-expressing oncolytic virus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets