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Stereotactic Adoptive Transfer of Cytotoxic Immune Cells in Murine Models of Orthotopic Human Glioblastoma Multiforme Xenografts
Published on: September 1, 2018
Replication-competent herpes simplex virus retargeted to HER2 as therapy for high-grade glioma
Eleonora Gambini1, Elisa Reisoli, Irene Appolloni
1Department of Experimental Medicine (DIMES), University of Genoa, Genoa, Italy.
Abstract:
Oncolytic herpes simplex viruses (HSVs) represent a novel frontier against tumors resistant to standard therapies, like glioblastoma (GBM). The oncolytic HSVs that entered clinical trials so far showed encouraging results; however, they are marred by the fact that they are highly attenuated. We engineered HSVs that maintain unimpaired lytic efficacy and specifically target cells that express tumor-specific receptors, thus limiting the cytotoxicity only to cancer cells, and leaving unharmed the neighboring tissues. We report on the safety and efficacy in a high-grade glioma (HGG) model of R-LM113, an HSV recombinant retargeted to human epidermal growth factor receptor 2 (HER2), frequently expressed in GBMs. We demonstrated that R-LM113 is safe in vivo as it does not cause encephalitis when intracranially injected in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, extremely sensitive to wild-type HSV. The efficacy of R-LM113 was assessed in a platelet-derived growth factor (PDGF)-induced infiltrative glioma model engineered to express HER2 and transplanted intracranially in adult NOD/SCID mice. Mice injected with HER2-engineered glioma cells infected with R-LM113 showed a doubled survival time compared with mice injected with uninfected cells. A doubling in survival time from the beginning of treatment was obtained also when R-LM113 was administered into already established tumors. These data demonstrate the efficacy of R-LM113 in thwarting tumor growth.
Insights
Engineered oncolytic herpes simplex viruses (HSVs) show promise for treating glioblastoma (GBM). R-LM113, targeting HER2-expressing GBM, demonstrated safety and doubled survival time in preclinical models.
Area of Science:
- Oncolytic virotherapy
- Cancer research
- Herpes simplex virus (HSV) engineering
Background:
- Oncolytic viruses offer a novel approach for glioblastoma (GBM) treatment.
- Existing oncolytic HSVs are often highly attenuated, limiting their efficacy.
- Targeting tumor-specific receptors can enhance safety and specificity.
Purpose of the Study:
- To evaluate the safety and efficacy of R-LM113, an engineered oncolytic HSV.
- R-LM113 is retargeted to human epidermal growth factor receptor 2 (HER2), common in GBM.
- Assess R-LM113's potential against high-grade gliomas (HGG).
Main Methods:
- Intracranial injection of R-LM113 into NOD/SCID mice models.
- Assessment of safety by monitoring for encephalitis post-injection.
- Evaluation of efficacy in a HER2-expressing, PDGF-induced glioma model.
Main Results:
- R-LM113 demonstrated in vivo safety, with no encephalitis observed in sensitive mice.
- Mice treated with R-LM113 showed doubled survival time compared to controls.
- Treatment of established tumors with R-LM113 also doubled survival time.
Conclusions:
- Engineered oncolytic HSV R-LM113 is safe and effective in preclinical HGG models.
- HER2-targeted oncolytic virotherapy shows significant potential for GBM treatment.
- R-LM113 effectively inhibits tumor growth and improves survival.
