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Faculty Profile

The Antibody Hero

Ron Levy's research has led to therapies that help the body's immune system kill cancer cells

Photo: Amanda Marsalis

By Krista Conger

Ron Levy, class of '68, was alone in the lab when his future revealed itself. "I can remember the day exactly," Levy says. "It was Thanksgiving Day, 1976. I developed a gel, saw the result and the next couple of decades of my life were before my eyes. I ran up and down the hall to show someone, but there was no one there."

Far from being overly grandiose, Levy's intuition was too limited. His finding -- that it was possible to generate monoclonal antibodies that would specifically recognize cancer cells inside the body and tag them for destruction -- paved a new direction in the field of oncology and the treatment of thousands of cancer patients. Later he would take the research one step further to show that vaccinating a person with proteins found only on cancer cells can incite a powerful immune response against the disease.

Levy was not always so prescient. As a freshman at Harvard, he told his parents back in Palo Alto that there were two subjects he had no interest in pursuing: teaching and medicine. But he took a couple of science courses, and then a couple more. His growing fascination carried him back to California to attend Stanford medical school, where he attracted the attention of cancer researchers Henry Kaplan, MD, and Saul Rosenberg, MD.

"There was no question that Ron would be a future star," says Rosenberg, emeritus professor of medicine and Levy's mentor. "He had an inquiring mind and very good clinical skills. It was easy to predict that he would be able to perform the difficult task of translating science to clinical practice."

Along the way Levy, now the Robert K. and Helen K. Summy Professor at Stanford and chief of the division of oncology in the Department of Medicine, has earned the respect of his scientific colleagues, fellow physicians and students, as well as nearly every major research award in the field of oncology. His most recent honor came in May when Levy received the 2004 J.E. Wallace Sterling Alumni Lifetime Achievement Award. But, despite the accolades, it is altruism rather than ambition that has guided his career.

"Everything that he does is oriented toward patients," says fellow professor of oncology and Levy's wife Shoshana Levy, PhD, whom he met in Israel while working with immunologist Michael Feldman. "He's always thinking of how research can be taken to the clinic. When he has a clinical question, he immediately begins to think about research that can be done to answer it. He's extremely focused on patient outcome."

It was this single-minded focus that led Levy in the 1970s to try to use the body's own defenses to fight cancer. The task was a difficult one. Cancer cells are cloaked in a mantle of respectability in the form of familiar cell surface proteins, or antigens, that often don't trigger internal defense mechanisms. Training the immune system to recognize and attack the traitors seemed an ideal treatment, if it were possible to spare healthy cells from the assault. Levy didn't shy away from the challenge.

"Ron persevered with his conviction that understanding the immune system could help fight cancer," Rosenberg says. "The problem has been that there are very few tumor-specific antigens." Without them, physicians had to rely on less-specific treatments such as surgery, chemotherapy and radiation, which can damage healthy cells.

In B cell lymphoma, however, each cancer cell sports an identical bull's-eye in the form of a cell surface receptor meant to recognize foreign invaders. Because the receptors are made up of randomly generated combinations of short protein segments, no non-cancerous cells should have the same marker as the cancerous clones. Levy used a new method of creating hybrid mouse-human antibody-generating cells to churn out large quantities of antibodies that would recognize and bind only to the cancer cells' receptors.

The method worked, and some patients treated with the antibodies were even cured. Although Levy and his colleagues started a company, IDEC Pharmaceuticals, in 1985 to market the treatment, generating a unique batch of antibodies for each lymphoma patient proved too cumbersome. The scientists discovered that a less-specific target found only on B cells also worked well without requiring analysis of each patient's tumor. In 1997, the resulting drug, Rituxan, became the first FDA-approved monoclonal antibody for cancer treatment. Currently, about 500,000 people each year receive the drug.

"It's been pretty amazing to see that whole transition from laboratory project to prescription drug," says Levy, who next began investigating whether vaccinating patients with tailor-made proteins from their own cancer cells could generate a home-grown immune response that would clear the tumor and bypass the need for antibody treatment.

The cancer vaccine quest continues

Although creating personalized vaccines can be labor-intensive and costly, a multicenter, double-blind clinical trial of the technique has shown promising early results. Levy believes that, if successful, the process can be streamlined to make it available to all lymphoma patients. Results of the trial, sponsored by Genitope Inc. -- a company founded by a former postdoctoral scholar of Levy's -- should be available within a year.

"If we can show it really works," Levy says, "people will get very clever about how to make it affordable and practical."

Not content to rest on his laurels, Levy is exploring another variation on personalized medicine: using the genetic fingerprint of cancer cells to predict which patients should be singled out for more aggressive treatment. Recently he and his colleagues found that the relative activity levels of just six genes could predict survival rates in seemingly similar cases of lymphoma.

"When Ron thinks about a disease, he thinks about the gaps in knowledge," Shoshana Levy says. "He's always questioning things to get to the root of them, and he tries to teach this to his students."

It's not all give and no take, though. Levy, who no longer has much time for the lab bench, depends on his students and postdocs for his most rewarding activity.

The most fun I have is still looking at primary data and figuring out how to ask the best questions and get the best answers," he says.

Asked if her husband will ever retire, Shoshana Levy laughs. "No," she says. "He enjoys his work too much."

 

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