A common virus given to patients intravenously can avoid immune detection, hitching a ride on immune cells in the blood, and find its way to tumor targets, where it replicates and destroys the cancerous cells, according to a report out today (June 13) in Science Translational Medicine.
“A lot of people in the field … had suggested that giving the virus into the blood couldn’t work because the antibodies would neutralize it straight away,” explained Alan Melcher, a clinical oncologist at the University of Leeds in the UK, who led the study. His team’s work now shows it is in fact an efficient way to target a tumor.
A laboratory-grown virus that can infect humans and evade the immune system might sound like it belongs on a bioterrorist’s must-have list, but in fact it’s what some cancer researchers have been waiting for. The viruses in question, including the one used by Melcher and colleagues, are adept at killing cancer cells but leave healthy tissue alone. “Often tumors get rid of genes to become immortal, and when they do that they actually become weak when it comes to viral infection,” explained John Bell, a specialist in Cancer Therapeutics at Ottawa Hospital Research Institute in Canada, who was not involved in the work.
But because these viruses, known as oncolytic viruses, commonly infect humans, most people have antibodies against them, and researchers feared that this might put the kibosh on any plans for their therapeutic use. Indeed in mice that were injected with reovirus—the virus used by Melcher and colleagues—preexisting antibodies prevented its delivery to tumors.
This turns out not to happen in humans, however. By injecting a large amount of reovirus into the blood, Melcher’s team was able to overcome the antibody neutralization. “I think they have demonstrated pretty nicely that one of the predicted barriers to therapeutic success isn’t in fact a barrier,” said Brain Lichty, a pathologist at McMaster University in Ontario, Canada, who also did not participate in the research. “[They’ve shown] that by simply dumping-in sufficient virus, even in people that have preexisting antibodies, they’re clearly able to deliver virus to tumors,” he said.
“It is a good example of why we have to do experiments in people and not just in animals,” added Bell.
Melcher and his colleagues administered large doses of reovirus to patients suffering from colorectal cancers that had metastasized to the liver. Ten patients, who were scheduled to have the liver tumors surgically removed, agreed to be dosed in the arm with reovirus after being told that, “in theory this virus might have some activity against your cancer, but it is absolutely not proven,” said Melcher.
Reovirus normally doesn’t cause any disease in humans, only rarely resulting in mild colds or stomach upsets. The patients, who received injections between a week and a month prior to surgery, suffered mild flu-like symptoms. Blood samples were taken at various time points and, after surgery, tumor tissue and surrounding normal liver were analyzed for the presence of the virus.
The researchers found that while virus particles in the serum of patients’ blood were mostly non-viable—no doubt neutralized by the patients’ antibodies—those particles that instead associated with immune cells, survived and were capable of replication in vitro. It is not yet clear whether the viruses entered the immune cells or attached to the outside, but live replicating virus detected in the tumors indicates that these immune-cell-associated viruses were escorted unharmed to the site of cancer.
The tumor cells also showed signs of cell death, suggesting that once the viruses reached the cancer, they were effective killers. Furthermore, it was only the tumor cells, and not normal liver tissue, that showed signs of both virus infection and cell death.
The big question—whether patients actually benefited from the therapy—remains unanswered. “To be honest, the numbers are too small to say,” said Melcher. “Unfortunately, in some of them their cancer has returned… but there is absolutely no way, from 10 patients, of saying whether the virus has made things any better or worse.” Much larger clinical trials are necessary, and these are now in development, he said.
Back in the laboratory, Melcher plans to test other types of cancer-killing viruses in a variety of tumor types to see which are best at killing which cancers. However, curing cancer isn’t going to be as simple as catching a cold. “We’re putting a very high dose of virus into the circulation [of the patients],” Melcher explained. “So sadly it’s not that catching these infections just from the normal course of things would help people with cancer. It needs to be targeted and deliberate treatment.”
R.A. Adair et al. “Cell Carriage, Delivery, and Selective Replication of an Oncolytic Virus in Tumor in Patients,” Sci. Transl. Med. 4, 138ra77, 2012.