The anthrax letter attacks of 2001 drew a lot of attention to the question of biological warfare, sparking fears that terrorist-funded biologists could create “superbugs,” bacteria or viruses designed to kill. But efforts to build designer bugs are not always malicious. In one unusual form of biological attack, researchers are engineering viruses to seek and destroy the cells that run amok in cancer patients. After more than 10 years of lab work, researchers in the field of “oncolytic therapy” have reached a sort of critical mass, deploying their designer viruses in a number of human trials.
The idea is astonishingly simple: let viruses do what they always do – but only to cancer cells. All viruses infect host cells and trick them into replicating the virus until the cells burst, releasing the new viruses. But unlike other viruses, oncolytic, or cancer-bursting, viruses reproduce in and destroy only cancer cells, leaving normal cells pretty much alone. “Viruses are a parasite, and they want to grow in cells that replicate very effectively to have the highest opportunity for themselves to replicate,” says Matt Coffey, chief scientific officer of Oncolytics Biotech in Calgary, Alberta. “Cancer cells fit that bill.”
Researchers usually begin by choosing a virus that replicates and kills cells aggressively, such as herpes simplex virus, tinkering with the genes it needs to reproduce so the organism grows exclusively in cancer cells, sometimes even targeting specific types of tumors. In some cases, genes are also added to the virus to give it an extra punch: the virus might produce a protein that, for instance, converts a nontoxic drug into a potent chemotherapeutic agent only in cancer cells or revs up the patient’s immune system to attack the tumor.
Several oncolytic viruses have entered human tests. Robert Martuza, a neurosurgeon at Massachusetts General Hospital and Harvard Medical School and a pioneer of oncolytic therapy, has done human safety tests of mutated herpes strains against brain cancer, for instance. Kenneth Tanabe, chief of surgical oncology at Massachusetts General, is participating in a liver-cancer clinical trial of a herpes strain owned by German biotech company Medigene. The company will also soon begin human tests of a strain targeted against brain cancer. Oncolytics Biotech is currently conducting clinical tests on how reovirus performs against an aggressive brain cancer called glioblastoma multiforme, as well as several different solid tumors. Cell Genesys, based in South San Francisco, CA, is developing cancer-targeted versions of adenovirus, often the culprit behind the common cold; one is already being tested in prostate cancer patients, and another should enter clinical trials against bladder cancer early this year.
One expectation of all these groups is that oncolytic therapies will not only treat previously incurable cancers but also help eliminate some of the worse aspects of cancer care. Although test patients sometimes suffer the low fevers or mild malaise typical of viral infection, none have shown the severe side effects associated with chemotherapy and radiation. Viral therapy should also enable doctors to destroy tumors without harming nearby tissue, a common problem with radiation and surgical treatments. Early results from the human tests have been promising; some patients experienced significant tumor shrinkage.
Still, oncolytic therapies face a major hurdle. As David Bartlett, chief of surgical oncology at the University of Pittsburgh Medical Center Cancer Centers, explains, “The single biggest drawback on all of these viruses is the host immune system reaction,” which attacks oncolytic viruses as it would any other virus. Many people have existing immunity to common viruses, such as herpes and adenovirus; were such people to undergo oncolytic therapy, their immune systems could destroy the viruses before they ever infected the cancer cells. The reaction could also preclude multiple rounds of treatment, since patients could develop immunity to the engineered virus after the first exposure.
Researchers are exploring ways of coping with patients’ immune reactions to oncolytic viruses. One possibility is to administer the virus directly to the tumor, largely bypassing the blood-based immune system. Or the immune system might turn out to be as much friend as foe. “The immune system will attack the virus,” says Martuza. “But at the same time, it will attack the cells the virus is growing in, so you’ll get a rejection not only of the virus but also of the cancer cells.”
It will almost certainly be several years before the first oncolytic viruses receive federal approval and become first-line therapies for cancer, but with more than a decade of experience behind them, researchers are optimistic that they will eventually succeed. “I don’t honestly know which of these viruses is going to work, and it may turn out that one will work for one type of cancer, one for another type of cancer,” says Martuza. “It almost doesn’t matter. It’s a blossoming field, and some of them will end up working.”