Last month, I wrote about using Salmonella to deliver anti-cancer compounds to tumours. Today, I’m sharing with you a paper on cancer-fighting viruses. Why the recent focus on microbiology and cancer? Because they’re much more interconnected than you would think and because they’re both so cool! (And maybe also because I’m a microbiologist and my husband is a cancer geneticist so it’s kind of like a mash-up of us.)
By now, most people will have heard of viruses that can cause cancer, the most well known example being human papillomavirus (HPV) and cervical cancer. But did you know that some viruses can also destroy cancers? These oncolytic viruses infect cancer cells and hijack the cell’s machinery to make lots and lots of new viruses. Eventually, the cancer cell becomes so full of viral progeny that it bursts open and dies. In doing so, it releases its cargo of oncolytic viruses to infect neighbouring cancer cells. When these viruses infect normal, healthy cells, the cells use their anti-virus immunity to prevent the invaders from taking over their machinery and making new viruses. In cancer cells, these anti-virus immune systems are weakened or disabled, giving the viruses free rein over the cells’ resources.
Vesicular stomatitis virus (VSV) is particularly good at attacking tumours. In preclinical studies, VSV has been successful in targeting a number of different cancers, including cancers of the prostate, breast, liver and colon. Furthermore, VSV has shown great potential in treating brain tumours, a disease for which treatment options are limited and prognoses are typically poor. One of the major obstacles to using VSV to destroy brain tumours is safety. While VSV preferentially targets and kills tumour cells, it also attacks normal brain cells, leading to harmful effects on motor coordination, behavior and other neuronal processes.
The neurotoxic effects of VSV seem to be primarily caused by a special protein on the surface of the virus, known as a glycoprotein or G protein. In a paper published this past week in the Journal of Virology, researchers at Yale University and Harvard University tried to overcome the neurotoxicity of VSV by engineering a hybrid virus. The researchers wanted to know if swapping out the G protein of VSV with the G protein from another virus would lessen the harmful effects of VSV on the brain while maintaining its tumour-killing abilities.
The VSV genome contains only five genes, one of which encodes the G protein. The researchers started by replacing the gene encoding the VSV G protein with the G protein gene from one of five different viruses: Lassa, Ebola, Marburg, rabies and lymphocytic choriomenigitis (LCMV). They then tested whether these new hybrid viruses could infect and replicate in brain tumour cells. Of the five hybrid viruses, the Lassa-VSV hybrid virus was the most promising because it had the greatest growth in tumour cells and strongly reduced growth in normal brain cells compared to native VSV.
To directly measure the neurotoxicty of Lassa-VSV, the researchers injected the hybrid virus into the brains of mice. As expected, mice injected with native VSV died within 10 days of the injection whereas mice injected with Lassa-VSV survived and remained healthy for more than 112 days post-injection. To say that this is a dramatic difference would be an understatement. This result provides pretty convincing evidence that that the neurotoxicity of VSV can be overcome by swapping in the G protein of Lassa virus.
Having established the superior safety of Lassa-VSV, the researchers next asked whether it is still capable of attacking brain tumours. Mice with brain tumours were treated with either Lassa-VSV or a placebo salt solution. Those receiving the placebo succumbed to the brain tumour in 35 days whereas those treated with Lassa-VSV survived for more than 80 days. When the researchers examined the brains of the mice treated with Lassa-VSV, they could barely detect any tumour cells, indicating that Lassa-VSV had effectively crossed the blood brain barrier and destroyed the brain tumour.
One of the main challenges of treating tumours is the possibility of tumour cells migrating to a new area. For example, cancer cells from melanomas, a deadly form of skin cancer, can often migrate to the brain where they can form a new tumour. The researchers did a clever experiment where they first implanted brain tumours at separate locations on the left and right sides of the mouse brain. They then injected Lassa-VSV into the right side of the brain and observed tumour growth on both sides. Eight days following the injection, the tumour on the right side of the brain was completely gone. Furthermore, the virus had migrated from the right side to the tumour on the left side of the brain and began to infect and destroy those tumour cells. The remarkable part of this experiment is that as the virus moved from the right to the left side, it left the brain cells in the middle completely unharmed.
The last thing the researchers did was to determine if Lassa-VSV could be used against other types of cancers. They showed that the virus was just as effective in destroying melanomas in the brain as it is with brain tumours like glioblastomas. Lassa-VSV could also infect prostate, colon, breast, bone and bladder cancer cells, suggesting that its tumour-killing potential may not be limited to melanomas and brain tumours.
Once in a while, I read a paper that literally makes me say “Wow!”. This is one of those papers simply because the results were so striking. But as with all preclinical models, translating these findings to patient studies will be a big challenge. Although oncolytic viruses have been extensively studied since the 1960s, there have been few human trials for virus-based therapies and even fewer therapies that have made it all the way to the clinic. Nonetheless, I am cautiously optimistic that all the research in this area will one day lead to improved, targeted treatments against cancer. Microbiology and cancer unite!
Wollmann G, Drokhlyansky E, Cepko C, & van den Pol AN (2015). Lassa-VSV chimeric virus safely destroys brain tumors. Journal of virology PMID: 25878115