Cancer's natural enemy
By Katherine Hobson
The proposition had intrigued researchers for years: Why not harness the power of the body's own immune system to fight cancer? Great concept, and one supported by research in animal models, but it proved devilishly difficult to translate into treatments for people. Many researchers tried, failed, and moved on, fearing it was too difficult to teach the body to attack its own cells, however deranged they might be.
But Ronald Levy, now chief of oncology at Stanford University School of Medicine, persisted, convinced that his theory would eventually lead to therapies. That persistence led to Rituxan, the first monoclonal antibody approved to treat cancer. Yet the drug, which is now the top-selling antitumor medication in the world, actually represents a step back from Levy's original idea and his current project: developing highly specific treatments customized for the unique signature of each patient's disease.
Warriors. Levy received his M.D. in 1968, three years before President Nixon's declaration of war on cancer. Many of the best medical minds were focusing on the disease, and research funds were abundant. Levy looked to the immune system for answers. He worked at the National Cancer Institute (news - web sites) and is now at Stanford, where he and his wife, Shoshana, have what he calls "mom and pop labs" (she's a cancer biologist). Specifically, he focused on components of the immune response called B-cells, each of which possesses a unique protein on its surface. When one of those cells reproduces uncontrollably--the hallmark of cancer--the resulting tumor is made up of cells all marked by the same surface protein. If you could some-how generate an antibody specific to that cell surface protein, Levy realized, you could target the cancerous cells but not kill the healthy cells, thus avoiding the toxic side effects of other treatments. "We were pretty optimistic that we would be able to find targets that the immune system would recognize," he says.
During the 1980s, he and his colleagues worked to make these customized antibodies in large enough quantity to give to the patient. "It was a great opportunity to straddle the fence between the bedside and the lab," remembers Richard Miller, then a member of Levy's lab and now CEO of Pharmacyclics, a Sunnyvale, Calif.-based biotechnology company. "We could run down the hall and treat the patient, then turn around and run back to the lab to run tests. Literally everything we were doing was new and uncharted." Levy's lab was known as a place where exciting things were happening, where students carried over their lab conversations into gatherings in the hot tub. "In an environment like Stanford, the people revered . . . can take your brain somewhere it hasn't been before," says Dan Denney, a Stanford postdoc at the time who now heads Genitope, a biotech company with which Levy works to test his current vaccine work. "He's really good at that."
Last hope. The antibodies were a lifesaver for many of the trial's patients, who tried the radical approach as a last-ditch attempt. "I was just about ready to bow out," says Philip Karr, who was 67 when he was treated. "I couldn't swim a width of the pool. Within a few days of treatment, I could swim a width, and then soon I was swimming the length of it." He's now 90, cancer free, and living in Santa Barbara, Calif., with his wife.
But despite its potential, mixing customized batches of antibodies was (and still is) enormously expensive and labor intensive. That's when Levy and his colleagues tripped across CD-20, the common surface protein found on most B-cells that could serve as a more generic target. "It was a lucky accident," says Levy. Rituxan, commercialized by IDEC Pharmaceuticals (now Biogen IDEC), a biotech whose founders included Levy and Miller, is a monoclonal antibody that targets CD-20 and destroys the cancerous cell. Used in combination with chemotherapy, it has sent many B-cell lymphoma patients into remission and added years to their lives. And it's being studied for other lymphomas as well. Levy is now working to discover why some patients don't respond to Rituxan.
But he never lost sight of his original idea to target antibodies at the patient's unique tumor. His current research includes the development of a lymphoma vaccine. Doctors would take out a portion of the cancer and identify the specific cell antigen. Instead of making antibodies in a lab, they'd let the body be the drug factory by reintroducing the antigen into the patient, attached to a kind of biological red flag that would signal the body to react and destroy the protein. Even if all goes well--and he will get a first peek at the data next year--therapy is a long way off. "I'm still not sure that we won't have a magic bullet," he says. "It's just that the time frame in which we expect things to happen is unrealistic." But Levy is nothing if not persistent in the face of seemingly unrealistic situations. The lymphoma patients his work has already helped are grateful for it.
By Katherine Hobson
The proposition had intrigued researchers for years: Why not harness the power of the body's own immune system to fight cancer? Great concept, and one supported by research in animal models, but it proved devilishly difficult to translate into treatments for people. Many researchers tried, failed, and moved on, fearing it was too difficult to teach the body to attack its own cells, however deranged they might be.
But Ronald Levy, now chief of oncology at Stanford University School of Medicine, persisted, convinced that his theory would eventually lead to therapies. That persistence led to Rituxan, the first monoclonal antibody approved to treat cancer. Yet the drug, which is now the top-selling antitumor medication in the world, actually represents a step back from Levy's original idea and his current project: developing highly specific treatments customized for the unique signature of each patient's disease.
Warriors. Levy received his M.D. in 1968, three years before President Nixon's declaration of war on cancer. Many of the best medical minds were focusing on the disease, and research funds were abundant. Levy looked to the immune system for answers. He worked at the National Cancer Institute (news - web sites) and is now at Stanford, where he and his wife, Shoshana, have what he calls "mom and pop labs" (she's a cancer biologist). Specifically, he focused on components of the immune response called B-cells, each of which possesses a unique protein on its surface. When one of those cells reproduces uncontrollably--the hallmark of cancer--the resulting tumor is made up of cells all marked by the same surface protein. If you could some-how generate an antibody specific to that cell surface protein, Levy realized, you could target the cancerous cells but not kill the healthy cells, thus avoiding the toxic side effects of other treatments. "We were pretty optimistic that we would be able to find targets that the immune system would recognize," he says.
During the 1980s, he and his colleagues worked to make these customized antibodies in large enough quantity to give to the patient. "It was a great opportunity to straddle the fence between the bedside and the lab," remembers Richard Miller, then a member of Levy's lab and now CEO of Pharmacyclics, a Sunnyvale, Calif.-based biotechnology company. "We could run down the hall and treat the patient, then turn around and run back to the lab to run tests. Literally everything we were doing was new and uncharted." Levy's lab was known as a place where exciting things were happening, where students carried over their lab conversations into gatherings in the hot tub. "In an environment like Stanford, the people revered . . . can take your brain somewhere it hasn't been before," says Dan Denney, a Stanford postdoc at the time who now heads Genitope, a biotech company with which Levy works to test his current vaccine work. "He's really good at that."
Last hope. The antibodies were a lifesaver for many of the trial's patients, who tried the radical approach as a last-ditch attempt. "I was just about ready to bow out," says Philip Karr, who was 67 when he was treated. "I couldn't swim a width of the pool. Within a few days of treatment, I could swim a width, and then soon I was swimming the length of it." He's now 90, cancer free, and living in Santa Barbara, Calif., with his wife.
But despite its potential, mixing customized batches of antibodies was (and still is) enormously expensive and labor intensive. That's when Levy and his colleagues tripped across CD-20, the common surface protein found on most B-cells that could serve as a more generic target. "It was a lucky accident," says Levy. Rituxan, commercialized by IDEC Pharmaceuticals (now Biogen IDEC), a biotech whose founders included Levy and Miller, is a monoclonal antibody that targets CD-20 and destroys the cancerous cell. Used in combination with chemotherapy, it has sent many B-cell lymphoma patients into remission and added years to their lives. And it's being studied for other lymphomas as well. Levy is now working to discover why some patients don't respond to Rituxan.
But he never lost sight of his original idea to target antibodies at the patient's unique tumor. His current research includes the development of a lymphoma vaccine. Doctors would take out a portion of the cancer and identify the specific cell antigen. Instead of making antibodies in a lab, they'd let the body be the drug factory by reintroducing the antigen into the patient, attached to a kind of biological red flag that would signal the body to react and destroy the protein. Even if all goes well--and he will get a first peek at the data next year--therapy is a long way off. "I'm still not sure that we won't have a magic bullet," he says. "It's just that the time frame in which we expect things to happen is unrealistic." But Levy is nothing if not persistent in the face of seemingly unrealistic situations. The lymphoma patients his work has already helped are grateful for it.
