Clinical advances in oncolytic virotherapy for pediatric brain tumors

Abstract

Malignant brain tumors constitute nearly one-third of cancer diagnoses in children and have recently surpassed hematologic malignancies as the most lethal neoplasm in the pediatric population. Outcomes for children with brain tumors are unacceptably poor and current standards of care-surgical resection, chemotherapy, and radiation-are associated with significant long-term morbidity. Oncolytic virotherapy has emerged as a promising immunotherapy for the treatment of brain tumors. While the majority of brain tumor clinical trials utilizing oncolytic virotherapy have been in adults, five viruses are being tested in pediatric brain tumor clinical trials: herpes simplex virus (G207), reovirus (pelareorep/Reolysin), measles virus (MV-NIS), poliovirus (PVSRIPO), and adenovirus (DNX-2401, AloCELYVIR). Herein, we review past and current pediatric immunovirotherapy brain tumor trials including the relevant preclinical and clinical research that contributed to their development. We describe mechanisms by which the viruses may overcome barriers in treating pediatric brain tumors, examine challenges associated with achieving effective, durable responses, highlight unique aspects and successes of the trials, and discuss future directions of immunovirotherapy research for the treatment of pediatric brain tumors.

Keywords: Brain tumors; Glioma; Immunotherapy; Oncolytic; Pediatric; Virotherapy.

Figure 1:. Timeline of clinical trials contributing evidence to the design and rationale of current clinical trials of oncolytic viruses for the treatment of pediatric brain tumors.

Each block represents a clinical trial. Lighter colored blocks represent trials that have been completed or terminated. Darker colored sections indicate active trials with estimated start and end dates as reflected on Clinicaltrials.gov, Gene Therapy Clinical Trials Worldwide (http://www.abedia.com/wiley/index.html), and (Chiocca, et al., 2004)as of January 2022. Unless otherwise noted, all trials are Phase 1. Age groups up to 21 years are designated pediatric. AdV adenovirus; ATRT atypical teratoid/rhabdoid tumor; CNS central nervous system; CP cyclophosphamide; DIPG diffuse intrinsic pontine glioma; GBM glioblastoma; GM-CSF granulocyte-macrophage colony-stimulating factor; GS gliosarcoma; HGG high-grade glioma; HSV herpes simplex virus; IFN-γ interferon-gamma; IT intratumoral (*indicates treatment may have been delivered peritumorally or into resection cavity); IV intravenous; LP lumbar puncture; MB medulloblastoma; MV measles virus; Peds pediatric; PNET primitive neuroectodermal tumor; Rad radiation; SQ subcutaneous; TMZ temozolomide. Created with BioRender.com