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Updated: Jan 8, 2026
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
An oncolytic herpes simplex virus armed with IL-12 for treatment of preclinical glioblastoma
Joseph W Jackson1, Bonnie L Hall2, Chaim Sneiderman3
1Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN 37920, USA.
Abstract:
Glioblastoma (GBM) is a devastating brain cancer with a 5-year survival rate of ∼5% despite current treatment regimens. Multiple oncolytic herpes simplex viruses (oHSV) have been designed for GBM therapy, but clinical trials have thus far met with limited success. A potential reason for this lack of efficacy is the immunosuppressive tumor microenvironment (TME) of GBM. Here we used an oHSV (KOS strain) armed with interleukin (IL)-12 (oHSV:IL-12) in an attempt to overcome this immunosuppression and analyzed the immunological and therapeutic impact in murine CT2A and GL261N4 orthotopic syngeneic glioma models. Unarmed oHSV failed to enhance survival in animals bearing syngeneic GBM tumors. However, oHSV:IL-12 induced significant and durable therapeutic benefits. TME interrogation following oHSV:IL-12 therapy revealed a significant accumulation of macrophages and cytotoxic T cells. Further investigation using single cell RNA-sequencing of GL261N4 tumors treated with either oHSV or oHSV:IL-12, indicated that oHSV:IL-12 induced robust macrophage accumulation within the TME and encouraged T cell receptor clonotype expansion compared to controls. These data point to the propensity of the IL-12 transgene to manipulate the myeloid compartment within the glioma TME, promote T cell expansion, and improve survival.
Insights
Oncolytic herpes simplex virus (oHSV) engineered with interleukin-12 (IL-12) significantly improved survival in glioblastoma models. This therapy enhanced anti-tumor immune responses by increasing macrophages and T cells within the tumor microenvironment.
Area of Science:
- Neuro-oncology
- Immunotherapy
- Virology
Background:
- Glioblastoma (GBM) is an aggressive brain cancer with poor prognosis.
- Current treatments for GBM have limited efficacy, partly due to the immunosuppressive tumor microenvironment (TME).
- Oncolytic herpes simplex viruses (oHSV) show promise but require strategies to overcome immune evasion.
Purpose of the Study:
- To evaluate the therapeutic and immunological impact of an interleukin-12 (IL-12) armed oHSV (oHSV:IL-12) in preclinical GBM models.
- To investigate the mechanisms by which oHSV:IL-12 modulates the GBM TME.
Main Methods:
- Utilized murine CT2A and GL261N4 orthotopic syngeneic glioma models.
- Administered unarmed oHSV and oHSV:IL-12.
- Performed TME interrogation and single-cell RNA-sequencing analysis.
Main Results:
- Unarmed oHSV did not improve survival.
- oHSV:IL-12 demonstrated significant and durable therapeutic benefits, enhancing animal survival.
- oHSV:IL-12 treatment led to increased macrophage and cytotoxic T cell accumulation in the TME.
- Single-cell RNA-sequencing revealed oHSV:IL-12 induced robust myeloid cell infiltration and T cell receptor expansion.
Conclusions:
- IL-12 armed oHSV effectively overcomes GBM immunosuppression.
- oHSV:IL-12 manipulates the glioma TME, promoting anti-tumor immunity and improving survival.
- This strategy holds potential for advancing GBM immunotherapy.
