Viruses are some of the most insidious creations in nature. They travel light: equipped with just their genetic material packed tightly inside a crystalline case of protein, they latch onto cells, insert their genes, and co-opt the cells’ energy-producing, gene-copying and protein-making machinery, using them to make thousands of copies of themselves. Once formed, the new viruses percolate to the cell surface, pinch off inside minuscule bubbles of cell membrane and drift away, or else they continue reproducing until the cell finally bursts. In any case, they go on to infect and destroy other cells, resulting in diseases from AIDS to the common cold.
Different viruses cause different diseases in part because each virus enters a cell by first attaching to a specific suction cup–like receptor on its surface. Liver cells display one kind of receptor used by one family of viruses, whereas nerve cells display another receptor used by a different viral family, so each type of virus infects a particular variety of cell. Cancer researchers have envied this selectivity for years: if they could only target cancer therapies to tumor cells and avoid damaging normal ones, they might be able to eliminate many of the noxious side effects of cancer treatment.
Some scientists, including ourselves, are now genetically engineering a range of viruses that act as search-and-destroy missiles: selectively infecting and killing cancer cells while leaving healthy ones alone. This new strategy, called virotherapy, has shown promise in animal tests, and clinical trials involving human patients are now under way. Researchers are evaluating virotherapy alone, as well as viruses “armed” with therapeutic genes that enable them to administer traditional chemotherapies solely to tumor cells. They are also developing methods to label viruses, or the cells infected by these viruses, to track the movement of the viral agents in patients.
One of the first inklings that viruses could be useful in combating cancer came in 1912, when an Italian gynecologist observed the regression of cervical cancer in a woman who was inoculated with a rabies vaccine made from a live, crippled form of the rabies virus. Physicians first injected viruses into cancer patients intentionally in the late 1940s, but only a handful appeared to benefit. Twenty years later scientists found that a virus that causes the veterinary disorder Newcastle disease shows a preference for infecting tumor cells and began to try to enhance that tendency by growing the viruses for generations in human cancer cells in laboratory culture dishes. Although critics countered that such viruses could be exerting only an indirect effect against cancer by generally activating an individual’s immune system and making it more likely to detect and kill cancer cells, reports continued to pop up in the medical literature linking viral infection and cancer remission. In the early 1970s and 1980s two groups of physicians described patients whose lymphomas shrank after they came down with measles.
The modern concept of virotherapy began in the 1990s, when researchers genetically modified viruses to selectively replicate in, and kill, tumor cells. Teams led by Frank McCormick of ONYX Pharmaceuticals in Richmond, Calif., and Daniel R. Henderson of Calydon in Sunnyvale, Calif., independently published reports showing they could target virotherapy to human cancer cells grafted into mice, thereby eliminating the human tumors. (ONYX is no longer developing therapeutic viruses, and Calydon has been acquired by Cell Genesys in South San Francisco, Calif.) Both groups used derivatives of an adenovirus, a cause of the common cold that has been intensively explored for virotherapy. (Other viruses under study include herpes simplex, measles, parvovirus, vaccinia, reovirus and the avian Newcastle disease virus.) Adenovirus is appealing in part because researchers understand its biology very well after years of trying to cure colds and of using the virus in molecular biology and gene therapy research. It consists of a 20-sided protein case, or capsid, filled with DNA and equipped with 12 protein “arms.” These protrusions have evolved over millennia to latch onto a cellular receptor whose normal function is to help cells adhere to one another.
Adenoviruses are distinct from the types of viruses usually used in gene therapy to treat inherited disorders. Gene therapy traditionally employs retroviruses to splice a functioning copy of a gene permanently into the body of a patient in whom that gene has ceased to work properly. Unlike retroviruses, however, adenoviruses do not integrate their DNA into the genes of cells they infect; the genes they ferry into a cell usually work only for a while and then are lost. Scientists have investigated adenoviruses extensively in gene therapy approaches to treat cancer, in which replication-defective derivatives of the viruses are exploited as vectors for transferring into cells genes that, for example, make cancer cells more susceptible than normal ones to chemotherapy. In general, tests involving adenovirus vectors have been safe, but regrettably a volunteer died in 1999 after receiving an infusion of adenoviruses as part of a clinical trial to test a potential gene therapy for a genetic liver disorder [see box on page 78].
Gene therapists have been working to tailor adenoviruses and other viral vectors, or gene-delivery systems, to improve their safety and reduce the chances that such a tragedy might occur again. It is perhaps even more essential for researchers such as ourselves, who are investigating virotherapy, to develop safer, more targeted vectors, because virotherapy by definition aims to kill the cells the viruses infect and thereby produce a new generation of infectious viruses, not just insert a therapeutic gene into them. Replicating in the wrong cells could be dangerous.