polly matzinger interview on NPR (danger model)
http://bioinfo.tg.fh-giessen.de/cancer/Interview-UweHobohm-PollyMatzinger-2009-8.mp3
Link to National Public Radio interview with Uwe Hobohm, PhD, and Polly Matzinger, PhD, broadcast on December 12, 2009, "Coley's Toxin, Cancer & Immunology."
SHE is working on the basis of a new theoretical view of the immune system. The new model starts with the idea that the driving force for an immune response is not the recognition of foreign antigen but the recognition of danger. The idea is that incoming viruses, bacteria, worms, and other pathogens create damage in the tissues they inhabit. These tissues relay alarm signals to activate the local sentries (the dendritic cells) to initiate immune responses. We are trying to find the tissue-generated alarm signals. We also are studying several implications of the model in such areas as pregnancy, autoimmune disease and transplantation.
TURNED ON BY DANGER
Turned on by Danger: Programme Notes
Dr Polly Matzinger is a sheep-dog trainer, former bunny girl, and one of the world's foremost immunologists. Four years ago she had a blinding moment of insight that led to a most extraordinary idea, the Danger Model. This film tells the story of how a high school drop out became a scientist, and had an idea that's reshaping the way people think about organ transplants and cancer.
Polly Matzinger left school under the cloud of being voted by her fellow students, "the person least likely to succeed in life". She spent ten years drifting, as a jazz musician, a dog trainer, and then a Playboy bunny. One evening she was serving drinks to a couple of scientists who were discussing their experiments. She asked a few incisive questions. One of the scientists was so impressed that he started a nine-month campaign to persuade her to go back to school to do science. Twenty years later she is chief of an immunology lab at one of America's leading research centres, the National Institutes of Health in Washington, and the main proponent of a radical theory.
For half a century doctors have been taught that the body's immune system attacks anything that's foreign. Not so, says Polly. The idea that the immune system operates like a rampaging skinhead, indiscriminately attacking foreigners, does not explain how we tolerate the millions of "good" bacteria that colonise our gut, nor does it explain why pregnant women do not reject their "foreign" babies. Instead, Polly Matzinger argues that the body will attack anything that attacks it. Our immune system responds, not to foreigness, but to danger.
Her theory points the way to a revolution in transplant surgery: it suggests ways of doing transplants without the fear of rejection and the need for immunosuppressive drugs. Horizon has filmed something that has never been done before: a mouse with a transplanted rat's heart inside him. Such transplants are so foreign they should be immediately rejected. Yet this mouse, on no drugs and with a completely normal immune system, has accepted the rat's heart as part of himself. Her "Danger Model" has also inspired novel cancer therapies; 32 year old Briton, Geoffrey Allen, has advanced cancer that has spread to his bones. At one of London's leading teaching hospitals he is being injected with bacteria in the hope that this will trigger a danger response, arousing his immune system to attack his cancer. And it does appear to be responding.
Her assault on long established beliefs has provoked a passionate debate. Polly Matzinger tells the moving story of her own, very unusual life and the extraordinary moment when it all came together.
ENLIGHTENED: Bendandi oversaw the five-year breakthrough cancer study in Pamplona
Dr. Maurizio Bendandi pokes fun at advertising slogans. "Pharmaceutical companies love to say, 'Treating cancer, one patient at a time,'" the 43-year-old observes. "But those companies are mass-producing drugs. We're the ones really doing it."
The "we" to whom Bendandi refers are the nine scientists on his team at work on customized cancer vaccines. A treatment that uses a patient's own tumor cells to provoke an immunological response, vaccines are one of the most promising developments in the fight against cancer, and a goal hotly pursued by researchers around the world. Bendandi and his colleagues at Spain's Center for Applied Medical Research and the University of Navarre Hospital have gone farther than most. In a five-year-long study — its results were described as "remarkable" by the Journal of the National Cancer Institute which published the report last September — the Pamplona-based group demonstrated that a customized vaccine could extend, perhaps indefinitely, the cancer-free period for patients with follicular lymphoma. In the wake of that success, Bendandi is preparing another study, one with an even more ambitious goal.
A cancer vaccine is not like the measles shot you get as a kid. Instead of inoculating a healthy person against a foreign body like a virus, cancer vaccines use parts of tumors to help the patients' immune systems recognize diseased cells. Follicular lymphoma, a generally slow-moving cancer of the immune system that affects roughly 5,000 Spaniards each year, presents an especially enticing target for vaccine researchers because its cells all carry a protein, called an idiotype, that distinguishes them from their healthy counterparts. Mixing the idiotype with other substances that trigger immunological responses, "the vaccine presents a tumor protein to the patients in such a way that their immune systems recognize it and destroy any cells bearing that protein," explains Larry Kwak, associate director of Cancer Immunology Research at Houston's MD Anderson Cancer Center and a leading vaccine researcher.
A vaccine for follicular lymphoma is not new. Stanford University's Ron Levy pioneered the effort more than 25 years ago, demonstrating that anti-idiotype antibodies could be produced in a laboratory and used to create a vaccine for humans that would trigger an immune response. In 1999 Kwak, then working at the National Institutes of Health (nih), modified the vaccine in a way that makes it easier for the immune system to recognize. His results were striking: the vaccine eliminated the residual tumor cells left after chemotherapy in 15 of his 20 patients. Now Bendandi, who worked with Kwak at the nih, has erected what he calls "the third pillar" of customized therapy by demonstrating that the vaccine produces not just molecular benefits, but clinical ones as well. In other words, the patients in his study lived cancer free for longer than expected.
Follicular lymphoma cannot currently be cured, but with chemotherapy and other treatments, a patient can usually achieve remission. The cancer almost always returns, however, and each subsequent remission tends to be shorter than the previous one. In 2001, Bendandi began vaccine therapy on 25 patients who had achieved a second remission with chemotherapy. The vaccine did not have any effect on five of the subjects, but the other 20 who did respond received a total of 10 vaccinations over 26 months. "Partway through the study, one of my patients — a hairdresser — came to me and said, 'I know the treatment is working,'" Bendandi recounts. "I asked her how she knew, because I had nothing conclusive yet. She said she knew because her first remission lasted 18 months, and her second remission had just reached 19 months." In fact, none of the 20 subjects relapsed while receiving the vaccine, and all had remissions that lasted significantly longer than their previous ones. Indeed, although the average second remission in follicular lymphoma lasts 13 months (in comparison with an average first remission of about two years), only a few of Bendandi's patients have relapsed since the vaccines stopped. All the rest are still in remission — including three who have been cancer free over five years.
In addition to showing that the vaccine can prolong remission, Bendandi's trial attempted to solve the long-standing problem of quantifying the results of custom-made treatments. Advanced drug trials require a control group, one whose members share key characteristics with those in the experimental arm, but who receive a placebo or another treatment rather than the one under study. According to Bendandi, randomized testing of custom-made vaccines would be meaningless because each patient in the experimental arm receives a different treatment. So he set about proving efficacy in another way. "The course of the study design was the first innovation," writes Dr. Dan Longo in an editorial appearing in the same journal that published Bendandi's study. "Each patient would be his or her own control. Second remissions longer than first would be an indication of therapeutic effect."
Not everyone is convinced by that logic. Dr. Robert Schwartz, an editor at the New England Journal of Medicine, says, "Using patients as their own control is a bit shaky, especially for follicular lymphoma." A Phase III randomized trial, more difficult but still possible to conduct even with customized vaccines remains, he says, "the gold standard for proof of efficacy." Dr. Kwak, who is conducting his own Phase III trial of a vaccine for the American pharmaceutical company Biovest, believes his former trainee's results support the case for a therapeutic lymphoma vaccine, but is skeptical about his methods. "Dr. Bendandi's study is important because it confirms previously reported results. But taken in isolation, it's a small study with no control group. It's not definitive."
Bendandi's vaccine also faces challenges common to other customized treatments: it's expensive (an estimated $34,000 per patient), it's difficult to make, and not all pharmaceutical companies (which make profits by mass-producing drugs) are able — or willing — to take on the work of producing a different vaccine for every patient. But with three Phase III clinical trials for idiotype vaccines under way in the U.S., and several other types of custom treatments in development (on March 29, an fda advisory committee found "substantial evidence" that a prostate cancer vaccine is effective, increasing the likelihood of its approval), hopes for cancer vaccines are running high.
Especially among the researchers developing them. "My trial was designed to have every chance to fail," says Bendandi. "If just one patient relapsed while receiving the vaccine, it would have been over. I would have needed a new job," he jokes. But the Italian-born physician is still working. In a few weeks he starts his new study, which is designed to test the vaccine's effectiveness in follicular lymphoma patients with an especially poor prognosis. Bendandi plans to administer the vaccine to participants until they relapse or die from a cause other than lymphoma. "This time," he says, "I'm going after a cure."
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