A new patient-derived orthotopic malignant meningioma model treated with oncolytic herpes simplex virus

Abstract

Background: Higher-grade meningiomas (HGMs; World Health Organization grades II and III) pose a clinical problem due to high recurrence rates and the absence of effective therapy. Preclinical development of novel therapeutics requires a disease model that recapitulates the genotype and phenotype of patient HGM. Oncolytic herpes simplex virus (oHSV) has shown efficacy and safety in cancers in preclinical and clinical studies, but its utility for HGM has not been well characterized.

Methods: Tumorsphere cultures and serial orthotopic xenografting in immunodeficient mice were used to establish a patient-derived HGM model. The model was pathologically and molecularly characterized by immunohistochemistry, western blot, and genomic DNA sequencing and compared with the patient tumor. Anti-HGM effects of oHSV G47Δ were assessed using cell viability and virus replication assays in vitro and animal survival analysis following intralesional injections of G47Δ.

Results: We established a serially transplantable orthotopic malignant meningioma model, MN3, which was lethal within 3 months after tumorsphere implantation. MN3 xenografts exhibited the pathological hallmarks of malignant meningioma such as high Ki67 and vimentin expression. Both the patient tumor and xenografts were negative for neurofibromin 2 (merlin) and had the identical NF2 mutation. Oncolytic HSV G47Δ efficiently spread and killed MN3 cells, as well as other patient-derived HGM lines in vitro. Treatment with G47Δ significantly extended the survival of mice bearing subdural MN3 tumors.

Conclusions: We established a new patient-derived meningioma model that will enable the study of targeted therapeutic approaches for HGM. Based on these studies, it is reasonable to consider a clinical trial of G47Δ for HGM.

Keywords: HGM; NF2; higher-grade meningioma; oHSV; orthotopic tumor model; patient-derived xenografts.