A Preclinical Evaluation of Neural Stem CellBased Cell Carrier for Targeted Antiglioma Oncolytic Virotherapy

Oncolytic adenoviral virotherapy (OV) is a highly promising approach for the treatment of glioblastoma multiforme (GBM). In practice, however, the approach is limited by poor viral distribution and spread throughout the tumor mass. To enhance viral delivery, replication, and spread, we used a US Food and Drug Administrationapproved neural stem cell line (NSC), HB1.F3.CD, which is currently employed in human clinical trials. HB1.F3.CD cells were loaded with an oncolytic adenovirus, CRAd-Survivin-pk7, and mice bearing various human-derived GBMs were assessed with regard to NSC migration, viral replication, and therapeutic efficacy. Survival curves were evaluated with KaplanMeier methods. All statistical tests were two-sided. Antiglioma activity of OV-loaded HB1.F3.CD cells was effective against clinically relevant human-derived glioma models as well as a glioma stem cellenriched xenograft model. Median survival was prolonged by 34% to 50% compared with mice treated with OV alone (GBM43FL model median survival 19.5 days, OV alone vs NSC OV, hazard ratio of survival 2.26, 95% confidence interval [CI] 1.21 to 12.23, P .02; GBM12 model median survival 43.5 days, OV alone vs NSC OV, hazard ratio of survival 2.53, 95% CI 1.21 to 10.38, P .02). OV-loaded HB1.F3.CD cells were shown to effectively migrate to the contralateral hemisphere and hand off the therapeutic payload of OV to targeted glioma cells. In vivo distribution and migratory kinetics of the OV-loaded HB1.F3.CD cells were successfully monitored in real time by magnetic resonance imaging. OV-loaded NSCs retained their differentiation fate and were nontumorigenic in vivo. HB1.F3.CD NSCs loaded with CRAd-Survivin-pk7 overcome major limitations of OV in vivo and warrant translation in a phase I human clinical trial for patients with GBM.