Related Experiment Video
Updated: May 23, 2026
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Interferon-β sensitivity of tumor cells correlates with poor response to VA7 virotherapy in mouse glioma models
Janne Ruotsalainen1, Miika Martikainen, Minna Niittykoski
1A.I. Virtanen Institute for Molecular Sciences, Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland.
Abstract:
In our recent study, replicative alphaviral vector VA7 was found to be effective against orthotopic human U87-glioma xenografts in an athymic mouse model eradicating the tumors with single intravenous (i.v.) injection. Here, we tested the efficacy of VA7 in immunocompetent orthotopic GL261 and CT-2A glioma models of C57BL/6 mouse in vivo. The cell lines were susceptible to VA7 infection in vitro, but GL261 infection was highly restricted in confluent cell cultures, and mouse interferon-β (IFNβ) pretreatment prevented the replication of VA7 in both cell lines. When mice bearing orthotopic GL261 or CT-2A tumors were administered neurotropic VA7, either i.v. or intracranially (i.c.), the vector was unable to infect the tumor and no survival benefit was achieved. Pretreatments with immunosuppressive cyclophosphamide (CPA) and rapamycin markedly lowered serum-neutralizing antibodies (NAbs) but had no effect on tumor infection or survival. Intracranial GL261 tumors were refractory also in athymic C57BL/6 mice, which have serious defects in their adaptive immunity. Implanted VA7-infected GL261 cells formed tumors with only slightly delayed kinetics and without improving survival thus excluding the participation of physical barriers and indicating robust host IFN action. Mouse and human IFNβ do not seem be species cross-reactive, which might limit the translational relevance of xenograft models in oncolytic virotherapy.
Insights
Replicative alphaviral vector VA7 showed efficacy in human glioma xenografts but failed in mouse glioma models. Host interferon response, not antibodies, limited VA7
Area of Science:
- Oncolytic virotherapy
- Immunology
- Neuro-oncology
Background:
- Replicative alphaviral vector VA7 demonstrated efficacy against human U87-glioma xenografts in athymic mice.
- The translational relevance of xenograft models for oncolytic virotherapy requires further investigation.
Purpose of the Study:
- To evaluate the efficacy of alphaviral vector VA7 in immunocompetent mouse glioma models (GL261 and CT-2A).
- To investigate the role of host immune responses, specifically interferon and neutralizing antibodies, in limiting VA7 efficacy in vivo.
Main Methods:
- Testing VA7 efficacy in orthotopic GL261 and CT-2A glioma models in C57BL/6 mice.
- Assessing VA7 infection susceptibility in vitro and in vivo after interferon-beta (IFNβ) pretreatment.
- Evaluating the impact of immunosuppressive treatments (cyclophosphamide and rapamycin) on VA7 efficacy.
- Comparing VA7 efficacy in immunocompetent and athymic C57BL/6 mice.
Main Results:
- VA7 failed to infect GL261 or CT-2A tumors and provide survival benefit in immunocompetent mice, regardless of administration route (i.v. or i.c.).
- Mouse interferon-β (IFNβ) pretreatment inhibited VA7 replication in both cell lines in vitro.
- Immunosuppressive treatments reduced neutralizing antibodies but did not improve tumor infection or survival.
- GL261 tumors remained refractory to VA7 even in athymic mice, suggesting a strong host interferon response.
Conclusions:
- Host interferon response significantly restricts alphaviral vector efficacy in syngeneic mouse glioma models.
- Species-specific differences in interferon activity may limit the translational relevance of xenograft models in oncolytic virotherapy.
- VA7 is ineffective in immunocompetent mouse glioma models due to host antiviral mechanisms.
