Immunologist Ralph Steinman was honored today by the Nobel Committee for his discovery of dendritic cells, a class of immune cells that help rally the body's natural defenses to fight disease. However, the prize is bittersweet for all who knew the 68-year-old scientist during his long career as a researcher and mentor at Rockefeller University in New York City. Steinman became the first winner to die, of pancreatic cancer, between his selection and the announcement of the coveted prize. And he fought his cancer using experimental therapies involving his discoveries.
This afternoon, the Nobel Foundation announced that Steinman's Nobel would stand. "The events that have occurred are unique, and, to the best of our knowledge, are unprecedented in the history of the Nobel Prize," the statement read. "According to the statutes of the Nobel Foundation, work produced by a person since deceased shall not be given an award. However, the statutes specify that if a person has been awarded a prize and has died before receiving it, the prize may be presented." Because Steinman was selected as a laureate before he died—even if the announcement came after he passed away—the Board of the Nobel Foundation is standing by its choice.
"Dendritic cells are the guys who are training the fighters," says Pawel Kalinski, an immunologist at the University of Pittsburgh in Pennsylvania, about their role in activating T cells, the body's immune sentries. Over decades, with Steinman often leading the way, the work transformed cancer research. Cancer vaccines either using or targeting dendritic cells are now the subject of numerous clinical trials, and the first-ever cancer vaccine to be approved in the United States—called Provenge, to treat prostate cancer—injects a patients' own dendritic cells back into their body. It went on the market last year.
Like all cancer vaccines, it's been a challenge to get dendritic cell immunotherapy to destroy tumors in people. The goal is to selectively activate certain T cells that are best-suited to target cancer.
One difficulty is that everyone's dendritic cells are different, so vaccines need to be personalized, making them expensive and labor-intensive to produce. Provenge, for example, costs $93,000 for three doses, and extends life by only about 3 months. Still, it "was a direct validation of Ralph's concept," says Kalinski, and vaccines designed more recently, he believes, are working better. A paper he published early this year in the Journal of Clinical Oncology describes a dendritic cell vaccine in advanced glioma, an aggressive form of brain cancer. Nine of the 22 people who received it were alive a year later without signs of progression, a rarity in a cancer as serious as this one.
Another strategy, which Steinman and others were studying, involves a therapy to target dendritic cells inside the body rather than taking them out and personalizing therapy for each patient. Those treatments are just starting out in clinical trials, says human immunologist Madhav Dhodapkar of Yale University, who's involved in that effort. It's been "somewhat of a roller coaster," he says, but "I think we're now beginning to see evidence for immune based approaches to work in cancer."
Steinman also pushed hard for testing therapies in people. "He was one of the first … to say, 'We've got to study humans,' " Dhodopkar says, something that had a lasting impact.
When Steinman was diagnosed with pancreatic cancer back in 2007, he knew he wanted to marshal his own dendritic cells in the fight. "He had great faith in dendritic cells," says Sarah Schlesinger, a physician and immunologist at Rockefeller. "He believed they would establish immunity, and that would cure him."
Steinman tried many experimental treatments, two of which involved dendritic cell therapies designed especially for him. A company, Argos Therapeutics, had a dendritic cell vaccine in trials for kidney cancer and personalized the vaccine for Steinman, even though his cancer was a different type; scientists at Baylor University Medical Center did something similar for another dendritic cell vaccine, which they were testing in melanoma. Both were official clinical trials that were closely vetted by the U.S. Food and Drug Administration. Steinman also tried a therapy called GVAX, which aims to recruit dendritic cells in the body. "There were dozens of colleagues around the country who helped," says Schlesinger.
Like many who worked with Steinman, Schlesinger described him as unfailingly generous. She first met him as a high school student, calling him out of the blue to seek work in his lab. He couldn't pay her, Schlesinger said, but would offer her vouchers for lunch. That was enough, and he became her lifelong mentor. "He would always introduce me as his colleague, and I would always introduce him as my boss."
Kalinski recalled his student days in the 1980s in his native Poland, when well-stocked libraries and science labs were largely nonexistent. "Every Monday I spent about 5 hours writing requests to people to send me their latest papers because our library was dysfunctional," he says. Steinman "always did respond," and also shipped samples of one of his first antibodies against dendritic cells.
Steinman kept an active lab right up to the end. Schlesinger visited him only a week ago with data about an HIV clinical trial of a dendritic cell vaccine, and Steinman was absorbed in what she had to share. While the Nobel Prize was well deserved, says Dhodapkar, "it obviously would have been nicer if he were able to hear the news himself."
Correction: This item has been clarified to reflect that scientists were working on a dendritic cell vaccine at Baylor University Medical Center.