Objective:

To evaluate the safety, efficacy, and immune correlates of intratumoral oncolytic viral therapy (OVT) in recurrent glioblastoma through cross-trial synthesis.

Background:

Recurrent glioblastoma (rGBM) remains a devastating diagnosis, with limited therapeutic options and a median post-progression survival of 6–9 months. Oncolytic viral therapy (OVT) is a novel therapeutic approach with dual cytolytic and immunomodulatory mechanisms with the potential to reshape the glioblastoma tumor microenvironment and enhancing antitumor immunity.

Design/Methods:

A systematic review was conducted of prospective clinical trials published between January 2015 and June 2024 evaluating intratumoral OVT in adults with rGBM or high-grade glioma. The trials used engineered intratumoral viruses, reported clinical outcomes, and incorporated immune correlative analyses. Eight studies met the inclusion criteria. The data synthesized assessed the safety, efficacy, and mechanistic patterns across viral platforms.

Results:

OVT demonstrated a favorable safety profile across all studies. Primarily grade 1–2 adverse events and no dose-limiting toxicities were noted. Median overall survival ranged from 9.5 to 21.3 months, with durable responses and long-term survival observed in a subset of patients. While objective radiographic reactions were uncommon, immune-related pseudo-progression was frequent, particularly with HSV1-derived vectors. Immune correlates, such as increased CD8⁺/CD4⁺ T-cell infiltration, interferon-gamma signaling, and upregulation of antigen presentation genes, were strongly associated with clinical benefit. Notably, therapeutic activity was observed in MGMT-unmethylated tumors, suggesting an immune-driven mechanism independent of chemotherapy sensitivity.

Conclusions:

Intratumoral OVT in rGBM is safe, feasible, and capable of inducing durable responses through immune reprogramming rather than direct oncolysis. The consistent correlation between immune activation and clinical benefit highlights the need for biomarker-driven patient selection, rational combination strategies, and immune-aware trial designs. As a platform, OVT holds significant promise in transforming the immunologic landscape of glioblastoma and highlights the merits of further study of next-generation immunotherapy.