Saturday, July 30, 2005

Can a Virus Kill Cancer?

Genetic engineers are turning nasty, infectious microbes into smart treatments for a deadly disease

In February, researchers at UCLA announced a clash of the titans, biochemically speaking: They turned one of the great scourges of humankind—HIV—into a hunter of another: cancer. In tests on mice afflicted with metastatic melanoma, a modified strain of HIV invaded cancer cells without infecting the rodents with AIDS. Around the same time, researchers at the Mayo Clinic in Rochester, Minnesota, announced similar results after engineering the measles virus to seek and destroy cancerous tumors while leaving healthy tissue unscathed.

The close timing of these breakthroughs speaks to the flurry of activity in the field of virotherapy, which exploits the tendency of viruses to attack cancer cells in a pitched battle that cancer often loses. With preliminary studies showing many of these viruses to be safe for humans, several universities and biotech firms are now conducting clinical trials of virotherapy.

As radical as it sounds, the idea of turning viruses loose on cancer actually predates the genetic technology that now fuels it. During the 1950s, scientists proved that adenovirus, a version of the common cold bug, was mildly effective against cervical cancer. But research was abandoned as chemotherapy gained prominence, and virotherapy was resurrected only after a study published in the journal Science in 1991 showed that a virus could be genetically modified to invade a tumor without inflicting disease.

The trick is to put the right virus in the right place—in other words, to deliver it to the malignancy, where it must penetrate the cancer cells, replicate, kill the cells, and invade adjacent cancer cells in mounting numbers—all without triggering the body's immune response. Direct injection is the typical shortcut, but some regions of the body, including the brain, are hard to reach this way. Using intravenous administration is the ultimate goal, because it's noninvasive and catches metastasized cancer, but this method is more likely to trigger the body's defenses and repel the therapy before it arrives at its destination.

“The immune system is the elephant in the room for the entire virotherapy field,” says Stephen Russell, director of the Mayo Clinic's molecular-medicine program. The engineered measles virus employed in the clinic's recent study was, in fact, administered successfully to mice via the bloodstream—one of the first such instances. To outwit the body's defenses, Russell devised a “targeted” measles virus, modifying its genome to express an antibody that shepherds it directly to the tumor.

Likewise, the HIV strain in the UCLA melanoma study was targeted, and researchers have since tailored it to seek and destroy prostate and melanoma cancers. “Basically, we put different hooks on the virus so it can hold on to different molecules,” says Irvin S.Y. Chen, director of the UCLA AIDS Institute.

While all this new work is promising, virotherapy could be years away from the medicine cabinet. Chen, for instance, won't begin human trials for at least another three years, and even therapies already in testing face several more years of experimentation and FDA scrutiny. But experts agree that the field is at a tipping point. The next few years of research should tell us whether or not the villainous virus is truly worth rehabilitating.