Web edition: February 10, 2013
Print edition: March 23, 2013; Vol.183 #6 (p. 18)
A tweaked virus that invades malignant cells has allowed patients with advanced liver cancer to survive for months longer than usual. Scientists report online February 10 in Nature Medicine that the virus can sabotage tumors and expose them to attack by the immune system.
The virus-based treatment will add a new weapon to medicine’s armory of tumor killers, says Ulrich Lauer, a hepatologist at the University of Tübingen in Germany, who wasn’t involved in the research. In particular, patients whose cancer has grown resistant to chemotherapy or other drugs might benefit, he says, because the virus’s mechanism of killing cancer cells is so different from existing therapies.
Viruses are natural human enemies that trigger a prompt immune response. Researchers have been trying since the 1990s to convert viruses into treatments aimed at tumor cells. The new study employs a partially disabled cowpox virus dubbed JX-594 that does not produce full-blown symptoms of the skin disease.
Study coauthor David Kirn, a physician and researcher at Jennerex Biotherapeutics in San Francisco, says earlier tests showed that the altered virus has a potent effect upon entering tumor cells. “It multiplies and blows the cell apart from the inside out,” he says. The immune system sees the cell’s debris as a mayday signal and sends sentinels that recognize suspicious proteins, including tumor proteins, and present them to enforcer cells. This triggers an immune attack on other tumor cells.
From 2008 to 2011, Kirn and his colleagues identified 30 people with advanced liver cancer that was no longer treatable with surgery. Survival for such patients is typically three to six months. Six of the patients had also failed to improve on other treatments and 19 had multiple tumors. Kirn says cancer had probably spread beyond the liver in all of them, even though doctors hadn’t spotted the tumor offshoots in some of the patients.
Each patient received three infusions of JX-594 into their liver tumors over a month. As part of the study, 16 got a large dose while 13 others received a smaller one. One patient dropped out of the trial for reasons unrelated to the cancer treatment.
Median survival was 14 months in patients getting the larger dose and seven months in the others. Overall, two-thirds were still alive after one year and at least four patients survived for more than two years, the data show. Those survivors included two whose tumors had failed previously to respond to medication. The predicted survival for such patients is two to four months, the authors note.
JX-594 caused only mild, flu-like symptoms in most patients. It preferentially hits tumor cells because the researchers had engineered it to lack an enzyme called thymidine kinase, which it needs. Cancerous cells produce an abundance of the enzyme, and the virus thrives in them, says study coauthor Tony Reid, an oncologist at the University of California, San Diego in La Jolla.
“We’re just hijacking the machinery and turning it into an Achilles’ heel of the tumor,” he says.
Kirn and his team have also tested JX-594 in small groups of patients with colorectal cancer and melanoma, the deadly kind of skin cancer. A larger trial of the treatment is already under way in liver cancer patients.
J. Heo et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nature Medicine. Online February 10, 2013.
B.H. Park et al. Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial. Lancet Oncology. Volume 9, June 2008, p. 533.
C.J. Breitbach et al. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature. Volume 477, September 1, 2011, p. 99.
Ongoing trial of cowpox virus treatment: [Go to]
Original trial of cowpox virus treatment: [Go to]