Coronavirus genetically redirected to the epidermal growth factor receptor exhibits effective antitumor activity against a malignant glioblastoma
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Published on: February 16, 2015
Monique H Verheije1, Martine L M Lamfers, Thomas Würdinger
1Virology Division, Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, The Netherlands.
Abstract:
Coronaviruses are positive-strand RNA viruses with features attractive for oncolytic therapy. To investigate this potential, we redirected the coronavirus murine hepatitis virus (MHV), which is normally unable to infect human cells, to human tumor cells by using a soluble receptor (soR)-based expression construct fused to an epidermal growth factor (EGF) receptor targeting moiety. Addition of this adapter protein to MHV allowed infection of otherwise nonsusceptible, EGF receptor (EGFR)-expressing cell cultures. We introduced the sequence encoding the adaptor protein soR-EGF into the MHV genome to generate a self-targeted virus capable of multiround infection. The resulting recombinant MHV was viable and had indeed acquired the ability to infect all glioblastoma cell lines tested in vitro. Infection of malignant human glioblastoma U87DeltaEGFR cells gave rise to release of progeny virus and efficient cell killing in vitro. To investigate the oncolytic capacity of the virus in vivo, we used an orthotopic U87DeltaEGFR xenograft mouse model. Treatment of mice bearing a lethal intracranial U87DeltaEGFR tumor by injection with MHVsoR-EGF significantly prolonged survival compared to phosphate-buffered saline-treated (P = 0.001) and control virus-treated (P = 0.004) animals, and no recurrent tumor load was observed. However, some adverse effects were seen in normal mouse brain tissues that were likely caused by the natural murine tropism of MHV. This is the first demonstration of oncolytic activity of a coronavirus in vivo. It suggests that nonhuman coronaviruses may be attractive new therapeutic agents against human tumors.
Insights
This study engineered a coronavirus, murine hepatitis virus (MHV), to target human glioblastoma cells using a soluble receptor-epidermal growth factor (soR-EGF) adapter. The modified virus demonstrated significant oncolytic activity in vitro and prolonged survival in a mouse glioblastoma model.
Area of Science:
- Virology
- Oncology
- Gene Therapy
Background:
- Coronaviruses possess characteristics suitable for oncolytic therapy.
- Murine hepatitis virus (MHV) naturally does not infect human cells.
Purpose of the Study:
- To engineer MHV for targeting and infecting human tumor cells, specifically glioblastoma.
- To evaluate the in vitro and in vivo oncolytic potential of the engineered MHV.
Main Methods:
- A soluble receptor (soR)-based expression construct fused to an epidermal growth factor (EGF) receptor targeting moiety was used to redirect MHV.
- The soR-EGF adaptor protein sequence was integrated into the MHV genome, creating a self-targeted recombinant virus (MHVsoR-EGF).
- In vitro infection and cell killing assays were performed on glioblastoma cell lines, and in vivo efficacy was assessed using an orthotopic U87DeltaEGFR xenograft mouse model.
Main Results:
- MHVsoR-EGF successfully infected human glioblastoma cells expressing EGFR in vitro.
- Infection led to efficient cell killing and progeny virus release.
- Treatment with MHVsoR-EGF significantly prolonged survival in mice with intracranial glioblastoma xenografts.
- No tumor recurrence was observed in treated mice, although some adverse effects in normal brain tissue were noted.
Conclusions:
- This study demonstrates the first in vivo oncolytic activity of a coronavirus.
- Engineered coronaviruses, like MHVsoR-EGF, represent a promising new class of therapeutic agents for human tumors.
- Further research is warranted to optimize safety and efficacy for clinical translation.
