Engineered Viruses Selectively Kill Cancer Cells

A single injection of a virus that has been genetically engineered to kill cancer cells can reliably infect tumors and leave healthy tissue unharmed, according to an early stage trial of 23 patients with metastatic cancers. The findings help lay the groundwork for a new type of cancer medicine using cancer-killing viruses.

Researchers injected different doses of the virus into patients with different types of metastatic cancers. After eight to 10 days, they biopsied tumor tissue from each patient and found that the virus was replicating itself in the tumors of seven of the eight patients who had received the highest dose, with no serious side effects. Several weeks after the injection, tumors in about half of the patients seemed to stop growing, and shrunk in one patient. The study is published today in the journal Nature.

While the study is not the first to test a cancer-killing viral therapy, it is the first to thoroughly document the behavior of the virus in patients’ biopsy tissue. The results confirm that viruses can be used to selectively target these cells.  

One reason tumors can grow unchecked is that they suppress the immune system. However, this also makes tumor cells more susceptible to viruses, which replicate inside the infected cell until it bursts. Physicians have known for more than a century that viral infection slows tumor growth, and in recent years they’ve used molecular biology techniques to reëngineer more effective cancer-killing viruses.

Most such viruses now in trials are injected directly into the tumor. But what researchers really need is a therapy that could be injected into the bloodstream and seek out metastasized cancer cells throughout the body, says David Kirn, chief executive officer at Jennerex, the San Francisco-based biotech company that funded the study.

To develop JX-594, the therapy in the new study, researchers at Jennerex started with a strain of vaccinia virus, which is adept at evading the immune system. (It was also used in the smallpox vaccine.) They then armed it with a gene encoding a protein called GM-CSF, which triggers an immune attack against cancer cells. They also added a second gene for beta-galactosidase, a marker protein with which they could track the virus’s replication.

The effect, says Kirn, was “a product that destroys tumors by multiple, complementary mechanisms.”

Researchers still don’t know how well the virus will combat cancer. Such early trials “are not supposed to determine efficacy, but obviously, everyone is looking,” says Samuel Rabkin, a virologist at Massachusetts General Hospital in Boston. Rabkin was not involved in the study. Patients whose cancers seemed to stabilize weren’t necessarily the ones in which the researchers found the virus replicating, he notes. “It is actually one of the large questions in the field—is the therapeutic effect directly related to the amount of virus replication in the tumor?”

Another concern is that if patients get more than one dose, the body might get better at fighting off the virus, which could disarm the therapy, says Nori Kasahara, a gene therapy researcher at the University of California, Los Angeles. “We just don’t know how long-lasting the therapeutic benefit will be,” he says. “If the immune system fights off the virus, then the tumor might just come back.” Kasahara also did not participate in the research.

Jennerex is already testing the therapy in larger trials. It recently completed a trial in liver cancer that significantly improved patients’ survival rates, Kirn says.

The current trial’s results don’t just bode well for JX-594, he says, but for the field of cancer-killing viruses overall. “We can now engineer a variety of different therapeutic products into this viral backbone.”