OH2 oncolytic virus: A novel approach to glioblastoma intervention through direct targeting of tumor cells and augmentation of anti-tumor immune responses

Abstract

Glioblastoma (GBM), the deadliest central nervous system cancer, presents a poor prognosis and scant therapeutic options. Our research spotlights OH2, an oncolytic viral therapy derived from herpes simplex virus 2 (HSV-2), which demonstrates substantial antitumor activity and favorable tolerance in GBM. The extraordinary efficacy of OH2 emanates from its unique mechanisms: it selectively targets tumor cells replication, powerfully induces cytotoxic DNA damage stress, and kindles anti-tumor immune responses. Through single-cell RNA sequencing analysis, we discovered that OH2 not only curtails the proliferation of cancer cells and tumor-associated macrophages (TAM)-M2 but also bolsters the infiltration of macrophages, CD4⁺ and CD8⁺ T cells. Further investigation into molecular characteristics affecting OH2 sensitivity revealed potential influencers such as TTN, HMCN2 or IRS4 mutations, CDKN2A/B deletion and IDO1 amplification. This study marks the first demonstration of an HSV-2 derived OV's effectiveness against GBM. Significantly, these discoveries have driven the initiation of a phase I/II clinical trial (ClinicalTrials.gov: NCT05235074). This trial is designed to explore the potential of OH2 as a therapeutic option for patients with recurrent central nervous system tumors following surgical intervention.

Keywords: DNA damage; Glioblastoma; Immune microenvironment; OH2; Oncolytic viral.