I n the beginning of the last century, scientists were surprised to discover that cancer patients infected with a viral illness sometimes experienced tumor regressions, as did patients given attenuated viral vaccines. By the end of the century, researchers performing early gene therapy experiments were using viruses as delivery vehicles, or vectors, to insert genes into cells, taking advantage of the viruses’ innate ability to infect cells, replicate, cause cell death, release viral particles, and spread. “In the fi rst human gene therapy trials in the 1990s, only nonreplicating viruses were used as vectors because of safety concerns,” said Evanthia Galanis, M.D., professor of oncology at the Mayo Clinic in Rochester, Minn. “This taught us an important lesson: Using nonreplicating viruses resulted in infection or therapeutic gene expression in only a small percentage of tumor cells. “Modifying viruses in a smart way to enable them to replicate and be as cancer specifi c as possible, while sparing normal cells, was the next step,” Galanis said. Because of these early trials, oncolytic, or cancer-killing, tumor viruses are now one of the most active areas of gene therapy research in cancer, with several proof-ofprinciple studies ongoing. “Viruses can be reprogrammed into oncolytic vectors by combining three types of modifi cation: targeting, arming, and shielding,” said Michael Barry, Ph.D., professor of medicine at the Mayo Clinic. The idea is that a virus that can replicate only in cancer cells will multiply within the cells and kill them, releasing new copies of the virus to surrounding cells when they die, thereby infecting other tumor cells locally and at distant sites. Viruses used for oncolytic cancer therapy include adenoviruses, vaccinia, herpes simplex type 1, Newcastle disease virus, measles, retroviruses, vesicular stomatitis virus, and reoviruses.