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Updated: Oct 16, 2026
Intranasal Delivery of Therapeutic Stem Cells to Glioblastoma in a Mouse Model
Published on: June 4, 2017
Treatment of intracranial gliomas in immunocompetent mice using herpes simplex viruses that express murine
S Andreansky1, B He, J van Cott
1Department of Microbiology, University of Alabama at Birmingham School of Medicine, USA.
Abstract:
This report describes a test of the hypothesis that the oncolytic effect of genetically engineered, replication competent herpes simplex viruses (HSV) depends both on cell destruction by the virus and an immune response to the tumor cells induced in an immunocompetent animal system. The oncolytic vector was a HSV recombinant virus in which both copies of the gamma 1 34.5 gene were replaced with the murine genes encoding the cytokine interleukin-4 (IL-4) or interleukin-10 (IL-10). The hypothesis predicted that if an immune response plays a role in survival following intratumoral treatment of tumor-bearing animals with HSV, expression of IL-4 should prolong survival whereas expression of IL-10 should reduce it. The results are that (1) these cytokines can be expressed by HSV in productively infected cells both in vitro and in vivo; (2) HSV-expressing IL-4 or IL-10 genes were able to infect and destroy glioma cells in vitro; (3) intracerebral inoculation of HSV expressing either IL-4 or IL-10 into syngeneic murine glioma GL-261 cells implanted in the brains of immunocompetent C57BL/6 mice produced dramatically opposite physiologic responses. The IL-4 HSV significantly prolonged survival of tumor bearers, whereas tumor-bearing mice that received the IL-10 HSV had a median survival that was identical to that of saline treated controls; (4) immunohistochemical analyses of mouse brains at 3 and 7 days after virus inoculation showed marked accumulation of inflammatory cells composed primarily of macrophages/microglia, with various proportions of CD8+ and CD4+ T cells, but few B lymphocytes. We conclude that the cytokines expressed from genes encoded in the viral genome influence HSV therapy of tumors and this is probably due to the host immune response. Thus, cytokine expression may be an important adjunct to tumor therapy utilizing genetically engineered HSV.
Insights
Genetically engineered herpes simplex viruses (HSV) expressing interleukin-4 (IL-4) prolonged survival in glioma models, while interleukin-10 (IL-10) did not, suggesting cytokines influence HSV oncolytic therapy via immune response.
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Genetically engineered herpes simplex viruses (HSV) are explored for oncolytic therapy.
- The role of the host immune response in HSV-mediated tumor destruction is not fully understood.
Purpose of the Study:
- To test if the oncolytic effect of engineered HSV depends on both viral cell destruction and induced immune response.
- To investigate the impact of expressing interleukin-4 (IL-4) or interleukin-10 (IL-10) via HSV on tumor-bearing animal survival.
Main Methods:
- Recombinant HSV vectors were created, replacing gamma 1 34.5 genes with murine IL-4 or IL-10 genes.
- In vitro studies assessed HSV's ability to infect and destroy glioma cells.
- In vivo studies involved intracerebral inoculation of engineered HSV into immunocompetent mice with gliomas.
Main Results:
- Engineered HSV successfully expressed IL-4 and IL-10 in infected cells both in vitro and in vivo.
- HSV expressing IL-4 significantly prolonged survival in tumor-bearing mice.
- HSV expressing IL-10 did not improve survival compared to controls.
- Immunohistochemical analysis revealed inflammatory cell infiltration, including macrophages and T cells, in mouse brains.
Conclusions:
- Expressed cytokines from the viral genome significantly influence HSV tumor therapy, likely through modulating the host immune response.
- Cytokine expression represents a potential adjunctive strategy for oncolytic virotherapy using genetically engineered HSV.
