Colon cancer kills 50,000 Americans every year, making it the third most deadly cancer in the U.S. Treatment options after hepatic metastasis has developed include surgery and chemotherapy, but these benefit only a minority of patients.

"You could think of this virus as a new generation of chemotherapy that is much more selective about what it attacks," said Daniel Y. Sze, M.D., Ph.D., assistant professor of radiology at Stanford University Medical Center, Stanford, Calif. "Standard chemotherapy kills some healthy cells along with the cancer. This engineered adenovirus is designed to kill only the cancer and not to harm healthy cells."

"Normally with gene therapy, a specific gene is spliced into a deactivated virus, and the virus acts as a vector, a vehicle to get the gene inside the body's cells," said Dr. Sze. "In this case, we're using the live virus itself -- without any extra gene -- as the treatment. Rather than inject it directly into the tumor using a syringe and needle, where it might not get distributed evenly, we inject it into the artery, so that the flow of blood carries it throughout the liver, treating the entirety of each [metastatic] tumor."

The attenuated live synthetic virus was designed to infect only cells with an abnormality in the tumor suppressor gene p53, a genetic abnormality that may be the basis for cellular susceptibility to cancer, Dr. Sze said. About 50 to 66 percent of malignant cells have abnormal p53 function.

Most patients felt sick as if they had a mild case of influenza for up to a week after the injection, said Dr. Sze. Because the virus retains the ability to replicate, it is very effective at killing tumor cells. When an infected malignant cell dies, it lyses, releasing copies of the virus that can then infect other malignant cells.

"The serendipitous finding was that although the lack of p53 makes a cell mean, aggressive and cancerous, it also can not recognize when it's been infected by a virus," said Dr. Sze. "That is its Achilles' heel: it makes the cell particularly susceptible to viral infection by this particular engineered virus."

The multi-center trial was a dose-escalation Phase I trial, meaning that its purpose was to determine whether the treatment is safe and what dose can be tolerated by patients. The trial included a Phase II extension, in which some patients were treated with a high dose. All 35 patients had gastrointestinal cancer -- most originating in the colon -- that had spread to the liver. Each had a life expectancy of approximately six months without this treatment. None were candidates for surgical removal of the liver metastases. Almost all had received chemotherapy, which was either unsuccessful or had worked only temporarily.

After receiving the genetically engineered virus, none of the patients experienced toxic symptoms to the point where therapy needed to be stopped, even at the highest dose level. Dr. Sze said the results indicate the therapy is safe and research can progress to further Phase II efficacy studies.

Although a Phase I trial is designed to test for safety only, the researchers found early evidence that viral therapy does suppress tumors when administered in higher doses. The median survival time of the 28 patients who received the highest doses given in the trial was 369 days, about 1 year. The average expected survival time was approximately 180 days, or about 6 months. The suggestion of a beneficial effect will need to be proven in subsequent trials.

Computed tomography imaging showed that the tumors appeared to grow slightly larger immediately after the treatment, which was suspected to be an inflammatory response to the viral infection. The tumors then slowly got smaller in size.

"The tumors shrank somewhat, but more impressive was that blood tests showed that abnormal proteins being secreted by the tumors either decreased significantly, or became completely undetectable," said Dr. Sze. "That suggests the tumors, although still visible on the computed tomography scan, are dying or dead."

In the Phase II study, due to start this year at the same institutions, investigators will treat cancer patients with the virus as well as chemotherapy to try to confirm the beneficial effects of the virus.

"This virus seems to have an additive affect with chemotherapy," said Dr. Sze. "It could be years before this treatment is ready for prime time, but it could eventually be a frontline therapy to treat various types of primary cancer, as well as tumors that have spread from the original site."