To many in biomedical research, the name Ron Levy is synonymous with one of the earliest cancer immunotherapies: tumor-attacking monoclonal antibodies. Indeed, if his vaccine work pays off, it will hurtle him into the scientific spotlight for the second time in his career.
As far back as 1975, when he joined the Stanford faculty, Levy was convinced that the key to defeating lymphoma lay in exploiting a "marker" protein unique to each patient's tumor cells. He envisioned two possible ways to do this. One was to create a custom vaccine--the work he is doing today. The other involved a brand-new lab technique, pioneered in England, in which researchers use mice to manufacture large quantities of antibodies genetically engineered to go after a single target. These are monoclonal antibodies.
As the 1980s dawned, Levy's team was making monoclonal antibodies to home in on the tumor markers of individual patients. The idea was to inject them as a highly selective, customized drug. The antibodies would ignore healthy cells, attacking only the cancer.
Then along came a patient who seemed a good candidate for either approach. Phil Karr was a retired engineer who had been treated at Stanford for several years. By 1980, his condition had deteriorated dramatically. Levy had samples of Karr's lymphoma cells, and after wrestling with himself over whether to try a vaccine or the monoclonal antibodies, he chose the antibodies.
Bingo. The results seemed miraculous. Within a month, Karr's tumors shrank and his energy returned. X-rays showed no traces of cancer. When the results came out in the New England Journal of Medicine, they set off fireworks. Journalists seized on the "magic bullet" metaphor. Venture capitalists rushed to launch companies to capitalize on the findings. "It helped start the biotech industry," Levy says. Karr's dramatic improvement led many to believe that a cure for all cancers was at hand.
What happened next has become an all-too-familiar scenario in the high-stakes biotech biz. Almost immediately it was clear that other research teams were not getting the same great results. Their monoclonal antibodies weren't attaching to the right targets and were prompting rejections in many patients. Making the antibodies was expensive and time-consuming, and scientists had difficulty attaching them to chemotherapy drugs and radioactive compounds. Expectations surrounding the new treatment plunged, as did the stock prices of companies formed to pursue it.
No one ever questioned Levy's findings or integrity. Still, rumors circulated that his "miracle cure" had been a fluke and even that the patient had died. Phil Karr is, in fact, alive and well, living in Southern California at age 87. And while other researchers had trouble replicating that success, many subsequent patients in the Levy lab responded well to the treatment. "We did it 50 more times," says Levy. "Three-quarters of the patients had significant remissions, and in five or six people the tumors never returned."
"It wasn't difficult for us to duplicate the remissions," recalls David Maloney, MD '85, PhD '91, a member of Levy's lab at the time and now an associate professor at the University of Washington. "But there was huge hype based on the successes we had. Others rushed in and tried the wrong targets, and it didn't work."
In the initial financial flurry set off by the Karr case, Levy and a former postdoc from his lab launched a company, IDEC Pharmaceuticals, to commercialize the new treatment. After several years of effort, IDEC found it couldn't make the custom antibodies efficiently enough to sell like a conventional drug. So IDEC changed course, making monoclonal antibodies against another, more common marker on B cells--no longer tumor-specific or unique to individual patients but far more efficient to make. Levy helped test the product, although he had divested himself of all holdings. IDEC and partner Genentech finally won fda approval to market it in 1997. Studies showed that the drug, Rituxan, shrank tumors by 50 percent or more in about half of all patients who received it.
After all the hype and the backlash, Rituxan became the first new treatment approved for lymphoma in two decades and the first monoclonal-antibody cancer drug cleared by the FDA. "Ron created a whole new paradigm for cancer therapy," American Cancer Society vice president John Stevens says. "If he were remembered for nothing else, that would be sufficient for most careers."
