Targeted release of oncolytic measles virus by blood outgrowth endothelial cells in situ inhibits orthotopic gliomas

Abstract

Malignant gliomas remain largely incurable despite intensive efforts to develop novel therapies. Replicating oncolytic viruses have shown great promise, among them attenuated measles viruses of the Edmonston B strain (MV-Edm). However, host immune response and the infiltrative nature of gliomas limit their efficacy. We show that human blood outgrowth endothelial cells (BOECs), readily expandable from peripheral blood, are easily infected by MV-Edm and allow replication of MV-Edm while surviving long enough after infection to serve as vehicles for MV-Edm (BOEC/MV-Edm). After intravenous and peritumoral injection, BOEC/MV-Edm deliver the viruses selectively to irradiated orthotopic U87 gliomas in mice. At the tumor, MV-Edm produced by the BOECs infect glioma cells. Subsequent spread from tumor cell to tumor cell leads to focal infection and cytopathic effects that decrease tumor size and, in the case of peritumoral injection, prolong survival of mice. Since MV-Edm within BOECs are not readily neutralized and because BOEC/MVEdm search and destroy glioma cells, BOEC/MV-Edm constitute a promising novel approach for glioma therapy.

Endothelial progenitor cells for cancer gene therapy

“…73,76 The tail vein injection of BOECs infected with an adenoviral/retroviral chimeric system resulted in transduction of subcutaneously. growing B16 cells overexpressing VEGF.…”

Oncolytic measles virus strains in the treatment of gliomas

“…Patients' immune response and the extent of intratumoral spread are possible limitations, which could decrease the antitumor efficacy of oncolytic viruses. Use of cell carriers such as endothelial cells could represent a possible solution to this problem [42,43]. In addition, combination with immunosuppressive agents and novel delivery methods such as convectionenhanced delivery could address some of these limitations.…”

Use of genetically engineered stem cells for glioma therapy

“…Systemically injected endothelial progenitor cells have been demonstrated to be able to target experimental gliomas and assimilate into the tumor vasculature (65,66). Endothelial progenitor cells have been genetically modified to produce oncolytic measles virus and tested as a potential anti-glioma therapy (67), or engineered to express cytotoxic anti-tumor genes (65). Embryonic stem cell-derived astrocytes have demonstrated intracranial migratory potential and therapeutic efficacy following implantation into subcutaneously established gliomas (68).…”