PVSRIPO(Duke University School of Medicine)

Glioblastoma (GBM) remains associated with poor outcomes, with a median survival of 15-18 months despite maximal safe resection, radiotherapy, and temozolomide. Therapeutic development has increasingly centered on overcoming drug resistance, intratumoral diversity, and restricted delivery across the blood-brain barrier. Progress in targeted therapy includes evaluation of EGFR inhibitors, multitarget tyrosine kinase inhibitors, and FGFR-directed agents, while rare molecularly defined subsets such as BRAF V600E and NTRK fusions offer tumor-agnostic precision approaches. JAK/STAT inhibition, PARP blockade, and PI3K/AKT/mTOR pathway modulation remain under investigation, although clinical benefit has been inconsistent. In parallel, precision oncology platforms incorporating multi-omic profiling, patient-derived organoids, and functional drug testing are refining therapy selection and supporting rational drug combinations. Adaptive clinical trial frameworks such as GBM AGILE and INSIGhT are accelerating the evaluation of novel agents within stratified cohorts,while emerging approaches including ChemoID-guided therapy, radiogenomic profiling, and digital modeling are beginning to influence translational endpoints. Immunotherapy continues to be an active area of research, though efficacy has thus far been limited. Immune checkpoint inhibitors have not yet demonstrated significant survival benefits as monotherapy, but combination strategies with vaccines, oncolytic viruses, and engineered cellular therapies are under evaluation. CAR T-cell therapies are advancing toward bispecific and armored constructs with locoregional delivery, while oncolytic viruses such as DNX-2401 and PVSRIPO demonstrate potential for durable responses in select patients. Looking ahead, progress is likely to arise from biomarker-informed, multimodal regimens that integrate targeted agents, next-generation immunotherapies, and precision-guided strategies, while embedding translational endpoints into trial design to address the complex biology and therapeutic resistance of GBM.

The poor prognosis of glioma underscores the urgent need for novel therapies. Recent advances in immunotherapy, especially in oncolytic virus therapy (OVT), have shown promising progress. In clinical trials, OVT has improved median overall survival up to 28.8 months. Different oncolytic viruses, including herpes simplex virus (HSV), adenoviruses, and polioviruses, have shown varying efficacy. HSV-based therapies, like G47Δ, have demonstrated promising survival outcomes, whereas polioviruses like PVSRIPO have excelled in eliciting strong immune responses. However, key challenges include ensuring the safety of viral vectors, overcoming the blood-brain barrier, maintaining long-term efficacy, and addressing excessive inflammation. This review aims to summarize the clinical challenges of OVT in glioma, with a focus on safety, delivery methods, immune response modulation, and the efficacy of various viruses.