*Review* **Personalizing Oncolytic Virotherapy for Glioblastoma: In Search of Biomarkers for Response**

**Eftychia Stavrakaki, Clemens M. F. Dirven and Martine L. M. Lamfers \***

Department of Neurosurgery, Brain Tumor Center, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands; e.stavrakaki@erasmusmc.nl (E.S.); c.dirven@erasmusmc.nl (C.M.F.D.) **\*** Correspondence: m.lamfers@erasmusmc.nl

**Simple Summary:** Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor. Despite multimodal treatment, the prognosis of GBM patients remains very poor. Oncolytic virotherapy is being evaluated as novel treatment for this patient group and clinical trials testing oncolytic viruses have shown impressive responses, albeit in a small subset of GBM patients. Obtaining insight into specific tumor- or patient-related characteristics of the responding patients, may in the future improve response rates. In this review we discuss factors related to oncolytic activity of the most widely applied oncolytic virus strains as well as potential biomarkers and future assays that may allow us to predict response to these agents. Such biomarkers and tools may in the future enable personalizing oncolytic virotherapy for GBM patients.

**Abstract:** Oncolytic virus (OV) treatment may offer a new treatment option for the aggressive brain tumor glioblastoma. Clinical trials testing oncolytic viruses in this patient group have shown promising results, with patients achieving impressive long-term clinical responses. However, the number of responders to each OV remains low. This is thought to arise from the large heterogeneity of these tumors, both in terms of molecular make-up and their immune-suppressive microenvironment, leading to variability in responses. An approach that may improve response rates is the personalized utilization of oncolytic viruses against Glioblastoma (GBM), based on specific tumor- or patientrelated characteristics. In this review, we discuss potential biomarkers for response to different OVs as well as emerging ex vivo assays that in the future may enable selection of optimal OV for a specific patient and design of stratified clinical OV trials for GBM.

**Keywords:** oncolytic viruses; glioblastoma; clinical trials; biomarkers; personalized oncolyticvirotherapy
