Healing Viruses

Researchers take cancer-fighting viruses from bench to bedside

More than 100 years ago, doctors noticed that some viruses have a remarkable ability to kill cancer cells while leaving healthy tissue almost unharmed. Since then, researchers have been trying to develop such viruses as treatments for cancer, but it’s only in recent years that their century of effort has begun to bear fruit. Now, a dozen oncolytic viruses are being tested in the clinic, with a couple poised to gain Food & Drug Administration approval in the next two years.

That brimming pipeline has many scientists in the field feeling confident. Most viral cancer agents in development have been shown to be safe and fairly effective, says Matt Coffey, cofounder of Oncolytics Biotech, one of three companies with cancer-killing viruses in Phase III human trials.

Until recently, it was widely believed that oncolytic viruses exerted their anticancer effects solely by replicating within malignant cells and then destroying them. But several studies have called that viewpoint into question, and at least one additional factor now seems to be at play, explains Richard G. Vile, an immunologist at the Mayo Clinic. In addition to killing cancer cells by replicating within them, the viruses provoke the immune system to more aggressively recognize and fight cancer. In other words, the oncolytic virus also works like a cancer vaccine, Vile explains.

“I think ultimately the strategy is going to be to use the virus infection to reduce the tumor burden—sort of a biologic surgery, initially,” says Timothy Cripe, an oncologist at Cincinnati Children’s Hospital Medical Center, where four oncolytic virus trials are taking place. Later in a course of treatment, he says, doctors may also use the viruses “to sensitize the immune response to keep the tumors from growing back.”

In recent studies, oncolytic viruses have shown substantial signs of efficacy. The results are good enough that Amgen recently acquired BioVex and its Phase III oncolytic virus candidate ( C&EN, Jan. 31, page 8). “If we do achieve the kind of clinical results that we are hoping for, it really will have a major effect on the field of oncology,” says Joe Miletich, Amgen’s senior vice president of R&D.

Many early victories in the field of oncolytic viruses were brought about by localized injections directly into tumors. Those localized doses are quite small compared with the systemic treatments that are being tested today. Only recently has it become viable to administer long courses and long doses of viruses systemically. That’s because producing enough of the viruses to conduct large, systemic trials is challenging.

Coffey notes that Oncolytics Biotech turned to Sigma-Aldrich for help in preparing enormous quantities of virus that can be given alongside traditional chemotherapy. He says Sigma-Aldrich took a huge risk when it got into the virus production game but that the gamble has paid off for the company. The chemical firm acquired a massive production facility that has made his company’s large clinical trials of oncolytic virus agents possible.

“With improved production techniques, we’re seeing the field grow much more rapidly just because you can suddenly entertain larger studies,” Coffey says. “You can mass-produce these now, which had been a challenge for some of these modified vectors before.”

However, several problems continue to limit the effectiveness of oncolytic viruses. For one, diagnostics that could be used to select the right virus for a patient are still at a very early academic stage, so doctors currently have no way to predict whether particular viruses will be effective for their patients. For example, JX-594, a modified vaccinia virus developed by Jennerex Biotherapeutics recently showed impressive efficacy in some cancer patients, but those results were not consistent, explains Evanthia Galanis, an oncologist at the Mayo Clinic (Nature, DOI: 10.1038/­nature10358).

Molecular tests that check for cancer cell types could help. For instance, Reolysin, a particularly innocuous virus developed by Oncolytics Biotech, prefers to replicate in cancer cells with an active Ras signaling pathway. Cells that have active Ras don’t produce a defensive protein called PKR, and that leaves them vulnerable to viral attack.

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Source: Chemical & Engineering News