Intranasal Delivery of Oncolytic Adenovirus XVir-N-31 via Optimized Shuttle Cells Significantly Extends Survival of Glioblastoma-Bearing Mice

SIMPLE SUMMARY: Glioblastomas (GBMs) are difficult-to-treat, deadly brain tumors and may infiltrate the whole brain. Cancer-killing (oncolytic) viruses have been used to treat GBMs. However, oncolytic virotherapy needs surgery, as the viruses have to be injected directly into the tumor. Human hepatic stellate cells were loaded with the oncolytic virus XVir-N-31 and applied into the noses of GBM-bearing mice via a non-surgical method. The virus-loaded cells rapidly migrated towards the brain tumor and invaded GBM cells located far away from the original tumor. In the brain, these shuttle cells released XVir-N-31, which then infected and killed the cancer cells. In consequence, the mice that received XVir-N-31-loaded shuttle cells via the nose showed delayed tumor growth and better survival. In addition, when the intranasal delivery was combined with an intratumoral injection of XVir-N-31, 25% of the mice did not develop any tumors and survived a long time. ABSTRACT: A glioblastoma (GBM) is an aggressive and lethal primary brain tumor with restricted treatment options and a dismal prognosis. Oncolytic virotherapy (OVT) has developed as a promising approach for GBM treatment. However, reaching invasive GBM cells may be hindered by tumor-surrounding, non-neoplastic cells when the oncolytic virus (OV) is applied intratumorally. Using two xenograft GBM mouse models and immunofluorescence analyses, we investigated the intranasal delivery of the oncolytic adenovirus (OAV) XVir-N-31 via virus-loaded, optimized shuttle cells. Intranasal administration (INA) was selected due to its non-invasive nature and the potential to bypass the blood–brain barrier (BBB). Our findings demonstrate that the INA of XVir-N-31-loaded shuttle cells successfully delivered OAVs to the core tumor and invasive GBM cells, significantly prolonged the survival of the GBM-bearing mice, induced immunogenic cell death and finally reduced the tumor burden, all this highlighting the therapeutic potential of this innovative approach. Overall, this study provides compelling evidence for the effectiveness of the INA of XVir-N-31 via shuttle cells as a promising therapeutic strategy for GBM. The non-invasive nature of the INA of OV-loaded shuttle cells holds great promise for future clinical translation. However, further research is required to assess the efficacy of this approach to ultimately progress in human clinical trials.