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.