Lassa-Vesicular Stomatitis Chimeric Virus Safely Destroys Brain Tumors

Abstract

High-grade tumors in the brain are among the deadliest of cancers. Here, we took a promising oncolytic virus, vesicular stomatitis virus (VSV), and tested the hypothesis that the neurotoxicity associated with the virus could be eliminated without blocking its oncolytic potential in the brain by replacing the neurotropic VSV glycoprotein with the glycoprotein from one of five different viruses, including Ebola virus, Marburg virus, lymphocytic choriomeningitis virus (LCMV), rabies virus, and Lassa virus. Based on in vitro infections of normal and tumor cells, we selected two viruses to test in vivo. Wild-type VSV was lethal when injected directly into the brain. In contrast, a novel chimeric virus (VSV-LASV-GPC) containing genes from both the Lassa virus glycoprotein precursor (GPC) and VSV showed no adverse actions within or outside the brain and targeted and completely destroyed brain cancer, including high-grade glioblastoma and melanoma, even in metastatic cancer models. When mice had two brain tumors, intratumoral VSV-LASV-GPC injection in one tumor (glioma or melanoma) led to complete tumor destruction; importantly, the virus moved contralaterally within the brain to selectively infect the second noninjected tumor. A chimeric virus combining VSV genes with the gene coding for the Ebola virus glycoprotein was safe in the brain and also selectively targeted brain tumors but was substantially less effective in destroying brain tumors and prolonging survival of tumor-bearing mice. A tropism for multiple cancer types combined with an exquisite tumor specificity opens a new door to widespread application of VSV-LASV-GPC as a safe and efficacious oncolytic chimeric virus within the brain. IMPORTANCE Many viruses have been tested for their ability to target and kill cancer cells. Vesicular stomatitis virus (VSV) has shown substantial promise, but a key problem is that if it enters the brain, it can generate adverse neurologic consequences, including death.We tested a series of chimeric viruses containing genes coding for VSV, together with a gene coding for the glycoprotein from other viruses, including Ebola virus, Lassa virus, LCMV, rabies virus, and Marburg virus, which was substituted for the VSV glycoprotein gene. Ebola and Lassa chimeric viruses were safe in the brain and targeted brain tumors. Lassa-VSV was particularly effective, showed no adverse side effects even when injected directly into the brain, and targeted and destroyed two different types of deadly brain cancer, including glioblastoma and melanoma. P atients diagnosed with high-grade gliomas in the brain have a poor prognosis and generally succumb to the tumor within a year (1, 2). Similarly, melanoma metastases in the brain also are a death sentence, with a similar or worse prognosis than glioma (3). Surgery, radiation, and chemotherapeutics can extend life modestly but often at the expense of quality of life. One approach to eliminating tumors is with oncolytic viruses, viruses that target and either destroy the tumor directly or genera...

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“…Replacing the glycoprotein of VSV with a foreign glycoprotein often results in virus attenuation in vivo. Indeed, the vast majority of cases where VSV recombinants express a heterologous viral glycoprotein (e.g., chikungunya virus, H5N1 influenza virus, Lassa virus, lymphocytic choriomeningitis virus, or Ebola virus) and were injected via intracranial route into mice or NHPs, no disease was observed (Mire et al, 2012;Muik et al, 2014;van den Pol et al, 2017;Wollmann et al, 2015). One exception is when VSV expressing the glycoproteins of the highly neurotropic Nipah virus was injected via an intracranial route into adult mice (van den Pol et al, 2017).…”

Mood stabilizers inhibit cytomegalovirus infection

“…After 2 h-incubation at 37°C to allow viral adsorption, inoculum was removed and cultures were washed three times with PBS before the addition of CMC overlay containing VPD, VCD, or vehicle at the specified concentrations. Five (mCMV) and 10 (hCMV) days later, the relative size of viral plaques was measured (n=60 plaques/condition), as previously described [42]. Each condition was tested at least in triplicate, and the experiment repeated twice.…”

Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update

“…This study suggest that more safety measures have to be taken when clinical testing of VSV-IFNb is done on patients with meningeal tumour deposits [60]. In general, the choice of the route of administration is very important when evaluating safety, as two studies have shown that intracranial injection of VSV-D M51 can be neurotoxic to Swiss-Webster mice and CD-1 nude mice [48,61].…”

“…VSV-G was also replaced by the glycoprotein from Ebola virus, Lassa virus, LCMV, rabies virus and Marburg virus in attempt to reduce neurotoxicity. VSV-LASV-GPC showed the most promising results by exhibiting no adverse side effects even when injected directly into the brain, and targeted and destroyed glioblastoma and melanoma [48]. VSV encoding glycoprotein genes from Nipah, chikungunya (CHIKV) and H5N1 influenza viruses also have been generated and tested.…”