Viruses Recruited To Fight Cancer

September 23, 1999

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By William J. Cromie
Gazette Staff

Antonio Chiocca (above) and his colleagues are attempting to make viruses effective enough to kill brain tumors without harming healthy cells. Photo by Kris Snibbe.

For almost 100 years, scientists have thought that viruses must be good for something besides causing disease. Following up on the idea that they might be used to infect cancer cells, researchers at Harvard Medical School have successfully experimented with viruses that kill brain tumors.

They also are testing the possibility that these bugs can be used to treat colon cancer that has spread to the liver, as well as other cancers.

"We think we can transform these pathogens into tumor killers by modifying their genes to infect malignant cells without harming healthy cells," says Antonio "Nino" Chiocca, an associate professor of surgery. Chiocca and research fellow Richard Chung report in the September issue of the Journal of Virology that they have engineered a virus that "spreads like wildfire in a tumor," while in normal cells it is a dud.

They used a herpes simplex virus, notorious for causing cold sores. But this dangerous and tricky bug can spread to healthy brain cells and lead to encephalitis and meningitis.

Working at Harvard-affiliated Massachusetts General Hospital in Boston, Chiocca’s team constructed a virus that other investigators at Georgetown University and the University of Alabama have begun testing for safety in humans.

This virus can kill tumor cells, but "it’s not as effective as we’d like it to be," Chiocca admits.

Researchers working with these organisms must walk a thin line between safety and efficacy. Nothing beats a so-called wild type, or unmodified virus, for destroying tumor cells but they also infect healthy cells. Last month, Chiocca reported infecting multiple brain tumors in rats with an organism that is more effective than the one now being tested in humans. Previously, this tougher virus was not safe enough to use in people.

Working with research fellows Chung and Yoshinaga Saeki, Chiocca managed to develop a molecular "promoter" that turns a virulent gene on and off. When the virus encounters tumor cells, the promoter stimulates the bug to reproduce itself at a rate close to that of a wild virus. When the same promoter-controlled gene gets into healthy cells, however, it stalls viral growth.

"We are getting close to a solution for the safety-versus-efficacy problem," Chiocca says. "We hope to finish animal tests by the of next year, and start safety testing in humans by 2001. If we run into difficulties, however, things could take twice as long."

From Rascals to Remedies
Chiocca expects to use this viral system on intractable brain tumors that do not respond to chemotherapy, radiation, or surgery. Known as gliomas, such malignancies kill more than 95 percent of the people they infect within a year. This cancer and other tumors of the brain and central nervous system are expected to kill 13,100 people in 1999.

Chiocca’s colleague at Massachusetts General Hospital, Kenneth Tanare, will try using the same type of engineered virus to destroy cancer cells that have spread from the colon to the liver.

Other researchers are investigating whether such bugs can be engineered to attack prostate tumor cells. "In chemotherapy, drugs that turn out to be effective but not too safe can be altered by chemists to increase the latter without sacrificing the former," Chiocca notes. "The same thing should be possible with viral systems."

There also are other ways to transform viruses from rascals to remedies. "We’re experimenting with taking the safest viruses and further modifying them so they increase the effects of cancer drugs and radiation," Chiocca notes. "That would make them more effective."

And it might be possible to infect people with viruses that carry genes capable of destroying blood vessels that supply tumors with nutrients and oxygen. Tumors require supporting blood vessels to survive and grow, and numerous drugs are being tested to starve them into regression (see story on page 1).

Before exploring the potential of blood-vessel-killing viruses, however, Chiocca has other problems to solve. Humans have evolved enormously effective defenses against invasions by viruses and bacteria. These natural barriers work to block viruses no matter how well they are engineered to fight cancers.

"When we first put viruses into tumors growing in the brains of rats, nothing much happened, even through we injected billions of them," Chiocca recalls.

He and his collaborators investigated proteins and various defense cells in the blood that might clear out viruses before they infect tumors. Then they tried to knock down these defenses with a drug called cyclophosphamide, used to prevent rejection of transplanted organs in humans. To their delight, they found that a single dose of the drug was enough to clear the way for the engineered viruses to reach their targets.

There should be no problem using the same drug with humans. "Besides its use to fight transplant rejection, cyclophosphamide serves as a chemotherapy drug and as a treatment for immune system diseases such as lupus," Chiocca comments.

At first, Chiocca’s group injected viruses directly into the tumor masses, but humans often have multiple tumors. "You can’t stick a needle in each tumor because of the potential for harming the brain," Chiocca points out.

What researchers want to do is put the viruses into the brain’s bloodstream and let them flow into vessels feeding the tumors. One way to do this is via a catheter, a long narrow tube threaded into the brain through a neck artery.

Physicians now rely on such catheters to carry camera lenses, balloons, and other instruments to the site of blood-vessel blockages in the heart and brain. "We should be able to use them to get viruses to almost any blood vessel feeding a tumor," Chiocca believes.

"Our results are very exciting so far," he says. "We are developing safe and effective viruses, we are testing ways to circumvent the body’s defenses, and we have a means of delivering viruses multiple times to multiple sites. Caution and rationality are still called for, but we hope we will soon be able to destroy one scourge with another."