Abstract
Viral oncolytic therapy for malignant brain tumors involves local intratumoral delivery of a genetically engineered virus with tumor cell–specific lytic activity. Promising preliminary results have been achieved in preclinical models with G207, a replication-competent herpes simplex virus type 1 constructed with multiple directed mutations. Although the safety of G207 has been demonstrated in adults, application of viral oncolytic therapy to children with brain tumors has been delayed because of previous lack of data concerning the impact of a replication-competent oncolytic virus on the developing mammalian brain. In this study there was no significant difference in long-term physical development, cognitive performance, or exploratory behaviors between mice that received intracerebral inoculation of G207 or control saline at 4 days of age. However, histological examination and magnetic resonance imaging revealed frequent unilateral ventriculomegaly ipsilateral to the site of injection in only the G207 group. These results suggest that although it is unlikely that G207 will have significant adverse effects on neurodevelopmental outcomes of pediatric patients with brain tumors, an initial study of G207 in children should exclude those patients with tumors in or near the ventricular system as well as patients less than 2 years of age. Furthermore, patients in such a study will need to be closely monitored for the development of hydrocephalus.
This study was supported in part by a Student Research Fellowship Award (A.E.R.) from the Pittman General Clinical Research Center at the University of Alabama School of Medicine, by a grant from the Pediatric Brain Tumor Foundation of the US (A.T.R.), and by funds from NIH grant P01CA071933 (G.Y.G, J.M.M.). The authors would like to thank Ken Fukuchi and Terry Lewis for assistance with conduct of the open-field maze, Frank Feng for assistance with conduct of the radial arm maze, and Matt Ward for assistance with the initial statistical calculations.