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<p>Oncolytic virotherapy represents a promising yet under-explored approach for precision cancer treatment, particularly when tailored to tumor-specific molecular profiles. Patients with high-grade isocitrate dehydrogenase (IDH) mutant astrocytomas have limited treatment options and poor prognoses. Here, we investigate the therapeutic efficacy of rQNestin34.5 v.2 (CAN-3110), an engineered oncolytic herpes simplex virus 1 (oHSV-1), in IDH1-R132H-mutant diffuse gliomas. We demonstrate that the IDH1-R132H mutation enhances glioma susceptibility to viral infection through upregulation of Nectin-1, the main HSV-1 entry receptor. Concurrently, IDH1-R132H-driven DNA hypermethylation suppresses interferon (IFN) signaling, creating a permissive microenvironment that facilitates viral replication and tumor cell apoptosis. In immunocompetent murine glioma models, intratumoral administration of rQNestin34.5 v.2 induces robust antitumor immune activation, including increased immune infiltration and systemic IFN-γ release. However, elevated expression of poliovirus receptor (PVR) and the immune checkpoint T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) on tumor-infiltrating leukocytes suggests a potential resistance mechanism to virotherapy. Combining rQNestin34.5 v.2 with TIGIT blockade enhances therapeutic efficacy compared to monotherapy, identifying IDH1-R132H as a potential predictive biomarker for oncolytic virotherapy response.</p>

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IDH1-R132H enhances oncolytic HSV-1 therapy by facilitating viral entry and immune activation in glioma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月17日

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  • Eleni Panagioti,
  • Hunter J. Kelley,
  • Alexander L. Ling,
  • Leinal Sejour,
  • Shikha Saini,
  • William F. Goins,
  • Daniel Roberts,
  • Sotiris Sotiriou,
  • J. Bryan Iorgulescu,
  • Karen O. Dixon,
  • Michael B. Yaffe,
  • Ioannis S. Vlachos,
  • Maria G. Castro,
  • Sean E. Lawler,
  • Gordon J. Freeman,
  • Vijay K. Kuchroo,
  • E. Antonio Chiocca,
  • Charles H. Cook

摘要

Oncolytic virotherapy represents a promising yet under-explored approach for precision cancer treatment, particularly when tailored to tumor-specific molecular profiles. Patients with high-grade isocitrate dehydrogenase (IDH) mutant astrocytomas have limited treatment options and poor prognoses. Here, we investigate the therapeutic efficacy of rQNestin34.5 v.2 (CAN-3110), an engineered oncolytic herpes simplex virus 1 (oHSV-1), in IDH1-R132H-mutant diffuse gliomas. We demonstrate that the IDH1-R132H mutation enhances glioma susceptibility to viral infection through upregulation of Nectin-1, the main HSV-1 entry receptor. Concurrently, IDH1-R132H-driven DNA hypermethylation suppresses interferon (IFN) signaling, creating a permissive microenvironment that facilitates viral replication and tumor cell apoptosis. In immunocompetent murine glioma models, intratumoral administration of rQNestin34.5 v.2 induces robust antitumor immune activation, including increased immune infiltration and systemic IFN-γ release. However, elevated expression of poliovirus receptor (PVR) and the immune checkpoint T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) on tumor-infiltrating leukocytes suggests a potential resistance mechanism to virotherapy. Combining rQNestin34.5 v.2 with TIGIT blockade enhances therapeutic efficacy compared to monotherapy, identifying IDH1-R132H as a potential predictive biomarker for oncolytic virotherapy response.