Ronald Levy M.D. ’68, Stanford School of Medicine professor and associate director of the Stanford Cancer Institute (SCI), unveiled the research that led to the breakthrough cancer medication Rituxan.

The event, taking place in Munzer Auditorium on July 9, was part of SCI’s Breakthroughs in Cancer seminar series, which brings to campus luminaries in translational cancer research from leading academic medical centers across the country. 

Levy was fascinated by the idea of harnessing the immune system to fight cancer while studying at Stanford and, later, Israel’s Weizmann Institute of Science in the late 1960s. He saw an image in “Nature” showing a mouse injected with a radiolabeled antibody. The image sparked the idea that a customized antibody could be engineered to selectively target the unique protein expressed on a clonal population of cancerous B-cells. 

Levy’s team used this novel approach to treat a patient, 67-year-old Phillip Karr, using immunotherapy. They developed a customized antibody targeting the patient’s lymphoma. Levy recalled the advice of his mentor, former Department of Radiology chairman Henry Kaplan, who said that “it is very important that the experiment work the first time.” It did, and Phillip Karr lived another 30 years.

Over the following decade, Levy’s team treated over 50 patients by engineering a specific, customized antibody for each. These customized antibodies were directed against the specific protein — which itself is an antibody — expressed on the surface of cancerous B-cells. From a business perspective, however, customized antibodies have several disadvantages, including the time, expense and labor required for their production, as well as the lack of a batch test for efficacy.

Two critical breakthroughs laid the groundwork for the eventual development of Rituxan. The first came in 1975, when Kohler and Milstein invented hybridoma technology, which facilitated the production of large quantities of antibodies by fusing a cell that creates a specific antibody with a cancerous cell, thereby endowing it with an indefinite lifespan. Some hybridomas created in 1975 continue to produce the same antibody today. This discovery “opened up a whole world of possibilities,” Levy said.

The second key breakthrough was the identification of a specific protein, termed CD20, which enabled the creation of an “off-the-shelf” antibody targeting all B-cell lymphomas, eliminating the need to develop a customized antibody for each patient’s lymphoma.

With the ability to produce antibodies on an industrial scale using hybridoma technology and CD20 as a ubiquitous lymphoma target, Richard Miller, a colleague of Levy, founded IDEC Pharmaceuticals to develop Rituxan, which became the first antibody approved for the treatment of cancer.

The drug was highly effective in clinical trials. Wendy Harpham, one of the earliest patients to receive Rituxan, survived 34 years following her diagnosis. Harpham’s case gave key insights to Levy and his team. They discovered that Rituxan can be used repetitively, and that it can be combined with chemotherapy given its mild side effect profile. 

Levy recounted that a clinical trial conducted by Sandra Horning, professor emerita, confirmed the substantial clinical benefit seen in an earlier trial conducted in France, helping to establish Rituxan as the new standard of care, and it continues to be largely unchallenged today. Since Rituxan’s approval in 1997, there has been a significant improvement in survival rates for non-Hodgkin’s lymphoma patients, Levy said, likely due to this novel treatment.

“This is the best part of the whole story of Rituxan — looking back over the years to see what public impact it had,” Levy said.

The battle against lymphoma continues, Levy stated. Since the introduction of Rituxan heralded the dawn of cancer immunotherapy, researchers have developed other antibodies and treatments. These approaches include “checkpoint inhibitors,” which prevent cancer cells from evading the immune system, and cancer vaccines, which help to stimulate the immune system to destroy cancer cells.

Levy concluded the seminar by noting that his life’s work is driven by advice from his former mentor, professor emeritus Saul Rosenberg. “Pick one disease. Study it well and it will take you to the ends of the earth,” Levy said, quoting Rosenberg.

A previous version of this story misstated Karr’s age at the start of treatment. The Daily regrets this error.