Advances and Future Expectations in Oncolytic Virus Therapy for Glioblastoma: A Systematic Review of Clinical Trials

Glioblastoma (GB), or grade IV astrocytoma, is the most prevalent primary tumor of the central nervous system (CNS). This systematic review aimed to investigate the efficacy and tolerability of virotherapy treatment for recurrent and progressive glioblastoma patients. We also examined recent progress in preclinical and clinical trials, and future perspectives.

We developed a search strategy using Medical Subject Headings (MeSH) terms and keywords. Inclusion criteria were English language published and ongoing clinical trials that involved patients undergoing virotherapy for glioblastoma. We searched through PubMed, Embase, Ovid, Scopus, Cochrane databases and https://Clinicaltrials.gov from inception until May 9^th, 2025. Two independent reviewers screened records, extracted data, and assessed risk of bias (ROB2). No meta-analysis was performed due to heterogeneity. PROSPERO CRD420250636791.

Of 975 records screened, 43 studies (24 published, 19 ongoing) enrolled 462 virotherapy patients. Most common adverse events: headache (n=145), fatigue (n=83) and fever (n=78). Risk of bias was moderate to serious in most studies.

We encountered several limitations, including high heterogeneity, reporting inconsistencies, and small sample sizes. Most patients experienced disease stabilization. However, objective response and complete remission occurred infrequently. A small proportion of patients achieved long-term survival, suggesting that virotherapy could be effective in specific subgroups. While oncolytic virus therapy is generally tolerated, neurotoxicity remains the most significant risk. Adverse effects were mostly Grade 1-2. Some trials (notably with HSV-1 or NDV) had severe events. Symptoms were often transient and manageable but need closely monitoring. However, the observed heterogeneity, limited data standardisation, and lack of randomized controlled trials, besides tumor heterogeneity, antiviral immunity and immunosuppressive microenvironment, necessitate further research to identify predictive biomarkers and optimize therapeutic protocols. We also suggest further trials on novel delivery methods, such as the nanoparticles, to enhance blood-brain barrier (BBB) penetration.