Modified cancer-killing virus avoids triggering immune system response
Viruses largely get a bad rap, but some may be helpful. Oncolytic viruses selectively hunt down and kill cancer cells, but this emerging therapy can be rendered ineffective or even dangerous if it alerts the immune system. Now scientists have tweaked these viruses to avoid detection by the immune system, allowing them to track down cancer even after it’s spread through the body.
On paper oncolytic viruses sound like a great treatment. These organisms are finely tuned to only infect cancer cells, leaving healthy cells alone – thus avoiding one of the main complications of radiation and chemotherapy.
But of course, things are rarely that straightforward. The human immune system is a well-oiled machine that filters out foreign invaders like viruses, regardless of whether they’re here to help us. The problem can be worse than just wiping out the viruses before they kill off the tumor – in the worst case scenario, the immune system can go into overdrive, resulting in a potentially fatal condition called a cytokine storm.
For the new study, researchers from Emory University and Case Western Reserve have re-engineered an oncolytic virus to allow it to avoid detection by the immune system. This “stealth bomber” approach could be deployed throughout the body to give the therapy a new advantage – hunting down metastatic cancers.
"The innate immune system is quite efficient at sending viruses to the liver when they are delivered intravenously," says Dmitry Shayakhmetov, lead author of the study. "For this reason, most oncolytic viruses are delivered directly into the tumor, without affecting metastases. In contrast, we think it will be possible to deliver our modified virus systemically at doses high enough to suppress tumor growth – without triggering life-threatening systemic toxicities.”
The researchers identified three sites on a commonly-used adenovirus to which natural immunoglobulin M (lgM) antibodies bind. By modifying these three regions, the antibodies could no longer bind to them, preventing the immune system being alerted to their presence.
The team then tested the new therapy in mice with grafts of human lung cancer cells, alongside a standard oncolytic adenovirus. In high doses delivered intravenously, the modified virus was tolerated by the mice, whereas the standard therapy triggered an immune response that killed that group within a few days.
About 35 percent of the animals treated with the modified virus had a complete response to the therapy, with no detectable tumors and an extended survival time. That’s a bit low, but at this stage the study was more focused on evading the immune system. The team says that the next steps in the work are to explore ways to increase the number of complete responders.
The researchers say that this virus could initially be tested in patients with metastatic lung cancer, with others to follow. Longer term, the study could lead to using these non-triggering virus vectors for a wider range of cancer types.
"This is a new avenue for treatment of metastatic cancers," says Shayakhmetov. "You can arm it with genes and proteins that stimulate immunity to cancer, and you can assemble the capsid, a shell of the virus, like you're putting in Lego blocks.”
The research was published in the journal Science Translational Medicine.