Author: Rachel Nuwer
In 1951, a 4-year-old boy with leukemia contracted chickenpox. His liver and spleen, swollen by the cancer, soon returned to normal, and his elevated blood cell count fell to that of a healthy child.
His doctors at the Laboratory of Experimental Oncology in San Francisco were thrilled by his sudden remission, but the blessing was short-lived. After one month, his leukemia returned and progressed rapidly until the child’s death.
In the early 1900s, not much could be done for cancer patients. Unless surgeons could excise a tumor, the disease typically spelled a swift and inevitable end. But in dozens of published cases over the years, doctors noticed a peculiar trend: Struggling cancer patients sometimes enjoyed a brief reprieve from their malignancies when they caught a viral infection.
It was not a coincidence. Common viruses sometimes attack tumor cells, researchers discovered. For decades, they tried to harness this phenomenon, to transform it into a cancer treatment. Now, after a long string of failures, they are nearing success with viruses engineered to kill cancer.
“It’s a very exciting time,” said Dr. Robert Martuza, chief neurosurgeon at the Massachusetts General Hospital and professor of neuroscience at Harvard Medical School. “I think it will work out in some tumor, with some virus.” Candidates are already in advanced trials, he noted.
Cancer cells are able to replicate wildly, but there’s a trade-off: They cannot ward off infection as effectively as healthy cells. So scientists have been looking for ways to create viruses that are too weak to damage healthy cells yet strong enough to invade and destroy tumor cells. It has been a long, difficult challenge.
Researchers started down this road in 1904, when they discovered that women with cervical cancer temporarily recovered when given a rabies vaccination. By midcentury, physicians were administering live viruses to cancer patients. They tried infecting terminally ill children with polio and adenovirus. They injected patients with concoctions from the feces of normal children, from sick chickens, and from “feline spleen suspension” of rural kittens infected with “cat plague.”
These experiments proved ill fated. The cancer returned, or — in the worst cases — the injections themselves caused “the development of lethal infection in the host,” according to a 1964 American Journal of Pathology report.
The field was abandoned for a time. But in 1991, Dr. Martuza seized upon the idea of using the herpes simplex virus (HSV-1) as a cancer-fighter.
The genome of HSV-1 is comparatively large and can accommodate a number of mutations and deletions. Dr. Martuza weakened the virus by removing some of its genes. The modified virus was injected into mice with brain cancer, and it did bring about remission. But most of the mice died of encephalitis.
In 1990, Bernard Roizman, a virologist at the University of Chicago, found a “master gene” in the herpes virus. When this gene is removed, the virus no longer has the strength to overcome healthy cells’ defenses. As it turned out, the modified virus was so crippled that it could only slow tumor growth.
Then, in 1996, Dr. Ian Mohr, a virologist at New York University, stumbled on a way of further altering Dr. Roizman’s crippled virus. He exposed it repeatedly to cancer cells until a new viral mutant evolved with the ability to replicate in those cells.
Dr. Mohr and a doctoral student, Matt Mulvey, then engineered a way for their virus to evade the immune system, making it an even more potent cancer-killing agent.
Unlike chemotherapy, which can diminish in effectiveness over time, oncolytic viruses multiply in the body and gain strength as the infection becomes established. In addition to attacking cancer cells directly, some also produce an immune response that targets tumors.
Today, several potential cancer-fighting viruses are in trials, including two in Phase 3 trials.
An engineered form of vaccinia — the viral agent that helped eradicate smallpox — is being tested against advanced liver cancer, the third leading cause of cancer deaths globally. In a recent trial, survival for patients treated with high doses of the virus, called JX-594, doubled to 14 months from 7, compared with that of patients treated with low doses.
“To see that kind of response in a randomized trial is simply unheard of,” said Tony Reid, the director of clinical investigation at the Moores Cancer Center of the University of California, San Diego, who has no financial ties to the virus’s manufacturer.
A herpes virus based on Dr. Mohr’s original discovery is in advanced trials against melanoma; initial data showed a 26 percent response rate in patient regression and survival. A reovirus is being tested against head and neck cancers, often difficult to treat.
According to the researchers, the side effects of treatment with these viruses are minimal, and include nausea, fatigue and aches. “In comparison to what happens with standard chemotherapy, flulike symptoms are very manageable,” said Dr. Reid, who has treated hundreds of patients with oncolytic viruses.
Oncolytic viruses are likely to find a place in medicine, especially paired with other therapies targeting difficult and aggressive tumors, said Gary Hayward, a virologist at the Johns Hopkins Herpesvirus Research Program. But the “biology is complex,” Dr. Hayward warned, and progress is likely to be incremental.
Dr. Mulvey now heads a firm in Baltimore testing viruses to fight melanoma and bladder cancer. The biggest challenge now, he said, is simply convincing others that the new treatment is “not science fiction.”
“Thankfully, that hurdle is diminishing,” he said.