Related Experiment Video
Updated: May 10, 2026
Stereotactic Adoptive Transfer of Cytotoxic Immune Cells in Murine Models of Orthotopic Human Glioblastoma Multiforme Xenografts
Published on: September 1, 2018
Multifaceted oncolytic virus therapy for glioblastoma in an immunocompetent cancer stem cell model
Tooba A Cheema1, Hiroaki Wakimoto, Peter E Fecci
1Brain Tumor Research Center and Molecular Neurosurgery Laboratory, Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Abstract:
Glioblastoma (World Health Organization grade IV) is an aggressive adult brain tumor that is inevitably fatal despite surgery, radiation, and chemotherapy. Treatment failures are attributed to combinations of cellular heterogeneity, including a subpopulation of often-resistant cancer stem cells, aberrant vasculature, and noteworthy immune suppression. Current preclinical models and treatment strategies do not incorporate or address all these features satisfactorily. Herein, we describe a murine glioblastoma stem cell (GSC) model that recapitulates tumor heterogeneity, invasiveness, vascularity, and immunosuppressive microenvironment in syngeneic immunocompetent mice and should prove useful for a range of therapeutic studies. Using this model, we tested a genetically engineered oncolytic herpes simplex virus that is armed with an immunomodulatory cytokine, interleukin 12 (G47-mIL12). G47Δ-mIL12 infects and replicates similarly to its unarmed oncolytic herpes simplex virus counterpart in mouse 005 GSCs in vitro, whereas in vivo, it significantly enhances survival in syngeneic mice bearing intracerebral 005 tumors. Mechanistically, G47-mIL12 targets not only GSCs but also increases IFN-γ release, inhibits angiogenesis, and reduces the number of regulatory T cells in the tumor. The increased efficacy is dependent upon T cells, but not natural killer cells. Taken together, our findings demonstrate that G47Δ-mIL12 provides a multifaceted approach to targeting GSCs, tumor microenvironment, and the immune system, with resultant therapeutic benefit in a stringent glioblastoma model.
Insights
A novel murine glioblastoma stem cell (GSC) model addresses tumor complexity. A genetically engineered oncolytic herpes simplex virus (G47-mIL12) significantly improved survival in glioblastoma models by targeting GSCs and the immune system.
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Glioblastoma (WHO grade IV) is an aggressive brain tumor with poor outcomes due to tumor heterogeneity, cancer stem cells (CSCs), aberrant vasculature, and immune suppression.
- Current preclinical models inadequately represent these glioblastoma complexities, limiting therapeutic development.
Purpose of the Study:
- To develop a more comprehensive murine glioblastoma stem cell (GSC) model that recapitulates key tumor features.
- To evaluate a genetically engineered oncolytic herpes simplex virus (G47-mIL12) in this stringent glioblastoma model.
Main Methods:
- Established a murine GSC model in syngeneic immunocompetent mice, mimicking tumor heterogeneity, invasiveness, vascularity, and immunosuppression.
- Administered G47-mIL12, an oncolytic herpes simplex virus armed with interleukin-12, to mice with intracerebral tumors.
- Assessed viral replication, tumor growth, survival rates, and immune responses (IFN-γ, regulatory T cells, angiogenesis).
Main Results:
- G47-mIL12 demonstrated similar in vitro replication to its unarmed counterpart but significantly enhanced survival in vivo.
- Mechanistically, G47-mIL12 targeted GSCs, increased IFN-γ release, inhibited angiogenesis, and reduced regulatory T cells.
- Therapeutic efficacy was dependent on T cells, not natural killer cells.
Conclusions:
- The developed murine GSC model effectively recapitulates critical glioblastoma features for preclinical studies.
- G47-mIL12 offers a multifaceted therapeutic strategy by targeting GSCs, the tumor microenvironment, and the immune system, showing significant promise in a challenging glioblastoma model.
