Recent approval of oncolytic herpes-simplex-virus (oHSV) therapy has opened a new era in the treatment of different cancer types. To circumvent the issues related to oHSV delivery via the bloodstream such virus neutralization, sequestration and inefficient extravasation, our accumulating data point out to the important role of loading oHSV into human mesenchymal-stem-cells (MSC) to effectively kill pediatric-brain tumor (PBT) cells in the brain. Although promising, these findings have raised questions for our MSC loaded-oHSV strategy to target heterogenous pediatric brain tumor-stem-cells (PBSC) and systemically deliver MSC loaded oHSV to the pediatric tumors in the brain? In this proposal, we will test the response and mechanism based efficacy of oHSV-TRAIL, a pro-apoptotic variant of oHSV that we have shown to kill a broad spectrum of tumor cells, in a panel of phenotypically diverse patient derived PBSC. Based on our exciting preliminary data that MSC-oHSV delivered via intracarotid artery (ICA) can track multiple tumor deposits in the brain, the fate and efficacy of ICA-delivered MSC loaded oHSV-TRAIL will be tested in different mouse models derived from PBSC. The proposed studies are likely to unravel the mechanism-based, targeted stem-cell mediated therapies for children with brain-tumors.