Human Bone Marrow-Derived Mesenchymal Stem Cells for Intravascular Delivery of Oncolytic Adenovirus Delta 24-RGD to Human Gliomas

Delta 24-RGD is an infectivity-augmented, conditionally replicative oncolytic adenovirus with significant antiglioma effects. Although intratumoral delivery of Delta 24-RGD may be effective, intravascular delivery would improve successful application in humans. Due to their tumor tropic properties, we hypothesized that human mesenchymal stem cells (hMSC) could be harnessed as intravascular delivery vehicles of Delta 24-RGD to human gliomas. To assess cellular events, green fluorescent protein-labeled hMSCs carrying Delta 24-RGD (hMSC-Delta 24) were injected into the carotid artery of mice harboring orthotopic U87MG or U251-V121 xenografts and brain sections were analyzed by immunofluorescence for green fluorescent protein and viral proteins (EIA and hexon) at increasing times. hMSC-Delta 24 selectively localized to glioma xenografts and released Delta 24-RGD, which subsequently infected glioma cells. To determine efficacy, mice were implanted with luciferase-labeled glioma xenografts, treated with hMSC-Delta 24 or controls, and imaged weekly by bioluminescence imaging. Analysis of tumor size by bioluminescence imaging showed inhibition of glioma growth and eradication of tumors in hMSC-Delta 24-treated animals compared with controls (P < 0.0001). There was an increase in median survival from 42 days in controls to 75.5 days in hMSC-Delta 24-treated animals (P < 0.0001) and an increase in survival beyond 80 days from 0% to 37.5%, respectively. We conclude that intra-arterially delivered hMSC-Delta 24 selectively localize to human gliomas and are capable of delivering and releasing Delta 24-RGD into the tumor, resulting in improved survival and tumor eradication in subsets of mice. [Cancer Res 2009;69(23):8932-40]