When Ralph M. Steiman was diagnosed with pancreatic cancer, he put to the test the theories he had developed about cancer and the immune system. With their help he survived longer than expected, but died three days before receiving the news of his Nobel Prize winning
One day Ralph M. Steinman peered through the microscope into a dish containing a cell culture and noticed something no one had seen before. It was in the early 70s when he was a researcher at Rockefeller University on Manhattan's Upper East Side. In those days, the scientists were still working on connecting the basic parts of the immune system assembly. They realized that it contained B cells, white blood cells that help identify foreign invaders, and T cells, which belong to another type of white blood cell that attacks these invaders. But the issue that puzzled the researchers was what triggers the activation of these T and B cells in the first place. Steinman caught a glimpse of what he thought could be the missing piece: strange cells, with thin, long arms, unlike any he had seen before.
Credit: Tammy Tulpa
It later turned out that his intuition was correct. Today, it is believed that these dendritic cells, as Steinman called them, play a crucial role in identifying invaders of the body and initiating the immune response against them. They hold the uninvited guests in their arms, swallow them and carry them to immune cells of other types. In fact, they "teach" the cells of the immune system what to attack. This discovery was a landmark that explained in an unprecedented level of detail how vaccine components work and elevated Steinman to the top of his profession.
In many ways, Steinman's story is typical: a brilliant scientist makes an important discovery that inspires a new generation of researchers. Indeed, his insight is noteworthy for its implications, both for science and for his personal life.
Over the years, Steinman came to believe that dendritic cells might serve as a vital weapon in the fight against some of the most heinous diseases, from cancer to AIDS. While it seemed that Steinman and an international network of colleagues were walking the right path to prove his righteousness, there was an unusual turn in the story.
In 2007, Steinman was diagnosed with pancreatic cancer, a merciless disease that kills four out of five patients within a year of diagnosis. In the end, the cells he discovered early in his career, and the friends he made along the way, not only helped him in his personal battle with cancer, but also gave him enough years of life to win a Nobel Prize. He died in September 2011, three days before a flashing light on his mobile phone told the family of the win.
A preconceived idea
Steinman did not study biology seriously before coming to McGill University as a student. But the subject captivated him from the first moment. The tiny world of immune system cells fascinated him and brought him to Zaneville A. Cohen's lab at Rockefeller University. Years later, Steinman presented in his office a quote from the mouth of Louis Pasteur, the famous 19th century microbiologist and vaccine expert: Le hazard ne favorise que les esprits prepares, which is commonly translated as: luck
Benevolence favors those whose minds are prepared in advance. "Ralph was well prepared in advance, so he was destined to make discoveries. And yet it was intuition that led him to conclude [that these cells] were important,” says Sara Schlesinger, Steinman's co-worker and longtime personal friend. It was his intuition and confidence in observation that allowed him to make the original discovery, and ultimately to gain the admiration of his peers.
After first discovering dendritic cells, Steinman spent the next twenty years convincing the scientific community of their importance, defining their modes of action and the way scientists should study them. "He fought—there's no other way to describe it—to convince that it was a separate entity," says Schlesinger, who joined Steinman's lab in 1977, while still a high school student. Even there, in that lab, people weren't convinced that the dendritic cells really existed, she says, because it was difficult to multiply them into larger doses. In those days, Steinman was still doing research in the laboratory with his own hands, and Schlesinger remembers how she sat across from him and examined the cells in a shared microscope. "He just liked to look at them," she says, smiling at the memory of the things. "There was real joy in every little discovery of his."
In the 80s Steinman, trained as a physician, began looking for ways to use his dendritic cell discovery to help people more directly. Over the following decades, as more and more researchers accepted the existence of cells, his lab expanded its focus of interest. He began researching vaccine components based on dendritic cells against HIV and tuberculosis, and researching cancer treatment. People who have contracted diseases against which there are vaccines, such as influenza or smallpox, and overcome this natural exposure, usually develop immunity for the rest of their lives. But diseases like AIDS, tuberculosis and cancer pose a more difficult challenge because they are apparently better at overcoming the immune system. In the case of HIV, the virus even uses the dendritic cells as hostages to do its dirty work. "Ralph used to say: 'We have to be smarter than nature,'" Schlesinger says. This meant helping the dendritic cells by giving them more targeted information about the virus or tumor the immune system was supposed to attack.
In the 90s, Steinman worked with Madhav D'Udafkar, now a researcher at Yale University, and with Nina Bardvaj, now at New York University, in developing a process for extracting dendritic cells from the blood and preparing them in advance using antigens - characteristic protein particles - of infections such as influenza or tetanus, and returning them to the body to strengthen the immune response. This method served as the basis for creating a vaccine against prostate cancer, Privenge, which was approved for use in 2010 and extended the lives of terminally ill patients - even if only by a few months. [See: "A new ally against cancer", Scientific American Israel, February-March 2012 issue.]
The final experiment
In early 2007, Steinman went to a scientific meeting in Colorado and stayed there for a family skiing vacation. During the vacation, he and his twin daughters suffered from stomach pains, but while his daughters recovered quickly, Steinman's illness continued. Immediately after returning home he developed jaundice. In the third week of March, the radiologists discovered in a CT scan a pancreatic tumor that had already spread to the lymph nodes. Steinman realized that his chances of recovery were slim: about 80% of pancreatic cancer patients die within a year.
"When he first told us about it, he said, 'Don't Google it, just listen to me,'" his daughter Alexis recalls. She felt as if someone had stabbed her. "He emphasized to the family that although it is a serious illness, he is in a very good position," she says. Unlike the average cancer patient, Steinman had free access to many of the world's best immunologists and oncologists, and perhaps more importantly, to their most promising treatment methods.
Schlesinger was "devastated" when she heard the news, but was quick to stand by her mentor. She, Steinman, and Michel Nussenzweig, their close colleague at Rockefeller University, began making phone calls and sharing the news with their colleagues around the world. Steinman was convinced that the surest way to cure any tumor was to develop immunity against it using one's own dendritic cells. The time they had at their disposal to prove him right was limited.
One of the first phone calls Steinman had after his diagnosis was with his partner of many years, Jacques Banchereau, who currently directs the Institute for Immunization Research at Baylor University in Dallas. Benshoro hastened to call researcher Anna Karolina Faluka from Baylor, who knew Steinman already in the 90s. Floka had an experimental component in development that she thought could help Steinman, but she had trouble meeting the personal challenge of trying to "separate the friend, the patient, and the scientist."
Schlesinger, in turn, called Charles Nicollet, a friend and research partner for many years who serves as the chief scientist of Argos Therapeutics, an RNA-based drug company that Steinman co-founded, located in Durham, North Carolina. A few minutes after the end of the phone call, a shocked Nicolet called his colleagues.
Nicolet's group developed a vaccine component based on dendritic cells that was in the second phase (intermediate phase) of a clinical trial for the treatment of advanced kidney cancer. Argos' treatment attempts to mobilize the patient's own dendritic cells to fight the cancer by exposing them to genetic material taken from the tumor. The exposure triggers these cells to recruit T cells for attack.
Steinman was scheduled for surgery to remove part of the pancreas in the first week of April 2007. The surgery is part of the traditional treatment for cases with a similar diagnosis called the Whipple procedure. Nicolet will need a part removed from the tumor to prepare the ingredient. The schedule left him just a few days to get FDA approval to include Steinman in his clinical trial. The team received the approval on time.
While the tumor cells were secured and Argos was busy preparing the treatment, a process that could take several months, Steinman began other treatments. Immediately after the operation, he began routine chemotherapy treatments based on the substance gemcitabine. Then, at the end of the summer, he signed up for a trial of GVAX, a dendritic cell-based compound being tested for pancreatic cancer. The compound, in the development of which Elizabeth Yaffe from Johns Hopkins University participated and whose treatment was conducted at the Dana-Farber - Harvard Cancer Center, utilizes an original antigen of the tumor, as Privenge does in the treatment of prostate cancer. In phase II of the clinical trial, conducted earlier, pancreatic cancer patients who received the compound lived an average of four months longer than patients who did not receive it, and some of them even lived several years longer. Over the course of two months, at the end of the summer, Schlesinger traveled with Steinman to Boston almost every week. “I remember walking through Boston on a day like today,” she says, looking out the window of her corner office at my sky in the bright blue October afternoon, “and thinking to myself, 'He's not going to see next fall,' and it was so sad.”
But autumn came and went, and Steinman's health remained relatively good. In September 2007, he won the Albert Lasker Prize for basic medical research, considered by many to be a forerunner of the Nobel Prize, and turned to a series of recorded interviews. In these interviews, he expanded on the promise of dendritic cells to fight cancer. He emphasized that an immune attack is a very targeted attack, very specific, and unlike chemotherapy is not toxic. "I believe this opens up the possibility of a whole new type of cancer treatment," he said. "But we need research and patience to uncover the laws and discover the principles."
Steinman sometimes exercised more patience than his colleagues believed was appropriate. At first he claimed that he needed to be treated very slowly so that the team could monitor his immune response after each treatment before starting the next one. But eventually Schlesinger and Nussenzweig convinced him that he simply didn't have enough time. If he dies, the experiment and the collection of results will end.
In November 2007, Argos' compound was completed, prepared by adding genetic material extracted from Steinman's tumor to cells taken from his blood. Steinman had just finished chemotherapy, and joined an Argos trial originally intended to treat renal cell carcinoma, but according to a special research protocol for a single patient.
At the beginning of 2008, Steinman began treatment using Floka's compound, which was originally developed against melanoma. The compound combined a selection of peptides (protein fragments) unique to the tumor, so Floka believed that it would be possible to adapt to Steinman's cancer using peptides from his tumor instead of melanoma antigens.
Other proposals for experimental treatments poured in from all over the world. "Everyone who could, brought the best they had," says Floka. In his decades of joint work with his colleagues, Steinman brought about the unification of this field of research, and now this network of scientists has turned to help one of its own. "People think that science is a singular process. In fact, it is a very social process," Schlesinger says. "The social nature of our work facilitates the realization of these enormous intellectual resources."
In addition to the usual treatment, Steinman eventually participated in four clinical trials that were being carried out at the time in cancer treatments based on dendritic cells, which were conducted on him under special conditions and most of which were not originally intended to treat pancreatic cancer. In addition, he participated in several other experimental immunological and chemotherapy treatments. Schlesinger, a member of Rockefeller University's Institutional Review Board (IRB), guided Steinberg's treatment through the necessary administrative maze at the IRB and the FDA, making sure he followed proper procedures. She also injected Steinman with the ingredients with her own hands when it was done at Rockefeller.
Steinman conducted the great experiment on himself just as he conducted other experiments in his laboratory: he was always meticulous about collecting the data, evaluating the evidence, and handing out instructions. Schlesinger still keeps the email threads from that time, with Steinman's messages, as usual, all printed in capital letters. He paid special attention to how his body responded to the treatment. In 2008, when Steinman received Floka's treatment, she came to visit New York, and after Schlesinger injected Steinman with the compound, the three of them went out to dinner. After the meal, Steinman insisted on stopping at the hotel where Floka was staying so he could show them the bruise that had developed on his leg around the injection site. "He was so excited about it," Schlesinger says. "He said, 'These are T cells'" - indicating that his body's immune system is responding to the compound - "'This is great!'"
The local swelling did show that Steinman's body responded to the compound, Floka says, but she's not sure the recruited T cells were unique to the tumor. She explains that all the compounds work through dendritic cells, but the difference between her compound and the other compounds Steinman tried is that instead of leaving the exposure to T cells to chance, the researchers manipulate the dendritic cells outside the body to improve the chances that they will train T cells to attack the tumor. When Schlesinger wasn't around to see the evidence for herself, she says that Steinman would send her passionate descriptions of the injection sites that included information about their shape, size and even how he felt each one.
The level of protein in the blood, which is used as a marker for the development of cancer (and whose value rose and fell during treatment), served as a measure of Steinman's approach. The second time the marker went down, he sent an e-mail with the subject line "We're back on the results of the experiment," an exclamation that typified Steinman's elation at a scientific victory.
But good news that satisfied Steinman the patient was never good enough to satisfy Steinman the scientist. The knowledge that the experiment on one person was not really a scientific experiment frustrated him immeasurably. The experimental treatments were given very close to each other, interspersed with traditional chemotherapy, so it was impossible to know what caused the tumor's biomarker to drop.
Still, Steinman collected some interesting data along the way. In one of the tests to monitor the immune system during the treatment with Floka's method, she found that about 8% of T cells, called CD8 cells (or killer T cells), target themselves uniquely to the tumor. The number doesn't sound big, but considering all the pathogens the body may encounter and attack, 8% "is a huge number," Schlesinger says. "I mean something, or a combination of things, inoculated him."
Death preceded by a few days
In June 2011 Steinman and his wife Claudia went to Italy to celebrate their 40th wedding anniversary. It was two months after he celebrated "Whipple Day" on the four-year anniversary of his surgery in April 2007. He had already far surpassed the average survival rate for cancer cases of his type.
In mid-September 2011, Steinman was still working in the lab, and arrangements were made to start another round of treatment with the Argos method. Then he got pneumonia. "When he was hospitalized he said: 'I might not get out of here,'" Alexis recalls. But after four and a half years of good health, she found it hard to believe that they only had a few days left together. He was still going over data from Rockefeller University on September 24th. He died on Friday, September 30, at the age of 68, as a result of respiratory failure caused by pneumonia. His body, weakened by cancer, could not overcome it.
The family was debating how to begin announcing this to a wide network of friends and colleagues around the world. They planned to arrive on October 3rd at his old lab, where he worked until recently, to tell the employees. But early that morning, before any of the family members woke up, there was a call from Stockholm. Steinman's silenced Blackberry was at that time with his wife. Early in the morning, while still sleeping, she glanced at the device to see if the notification light was flashing. At exactly that moment, an email arrived politely announcing that Steinman had won the Nobel Prize in Physiology or Medicine for 2011.
The first reaction was "that we all shouted together the word that starts with the letter Z," says Alexis. Her second thought was: "Let's go wake up Dad."
But in the rest of the world, the award committee's announcement did not seem unusual: articles were written and statements were published describing Steinman and the other two laureates, Bruce Butler of the Scripps Research Institute and Jules Hoffmann of the French National Center for Scientific Research. Only a few hours later, the story of Steinman's death surfaced and hit the headlines. The rules of the award state that the award cannot be given posthumously, but if the groom or bride of the award dies between the announcement in October and the ceremony in December, they remain on the list. Due to the unusual timing, the committee convened for a discussion that aroused great interest and announced, late that day, that Steinman would remain the winner.
A few days after the announcements of Steinman winning the Nobel and his death caused waves in the media, pancreatic cancer also took the life of one of the founders of Apple and its CEO Steve Jobs. Jobs, who had a rare form of the disease, a neuroendocrine tumor that develops at a slower rate, lived eight years after diagnosis, a period close to the average for patients with this type of cancer. However, Steinman survived much longer than expected. "There is no doubt that something extended his life," Schlesinger says.
Now the researchers are trying to figure out what it was. In early 2012, Baylor University established the Ralph Steinman Center for Cancer Vaccine Compounds and Floka is developing a clinical trial to treat pancreatic cancer patients using the same compound she helped create for Steinman. At Argos, Nicolet continues with full vigor in the development of the compound for kidney cancer: "There is a sense of obligation to Ralph to continue with it." In January 2012, they begin phase III of the clinical trial with the compound that Steinman tried.
Schlesinger believes the intervention of her colleagues ultimately contributed. "The scientific message is that the immune system works," she says. But the final lesson is one that Steinman loved to preach. "He used to tell people that there were so many other things that still needed to be discovered," she recalls. "And indeed there is and there is."
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About the author
Kathryn Harmon is an associate editor at Scientific American.
And more on the subject
Identification of a Novel Cell Type in Peripheral Lymphoid Organs of Mice, Vol. 1: Morphology, Quantitation, Tissue Distribution. Ralph M. Steinman and Zanvil A. Cohn in Journal of Experimental Medicine, Vol. 137, no. 5, pages 1142-1162; May 1973. www.ncbi.nlm.nih.gov/pmc/articles/PMC2139237
Taming Cancer by Inducing Immunity via Dendritic Cells. Anna Karolina Palucka et al. in Immunological Reviews, Vol. 220, no. 1, pages 129-150; December 2007. http://onlinelibrary.wiley.com/doi/10.1111/j.1600-065X.2007.00575.x/full
Dendritic Cell-Based Vaccination of Patients with Advanced Pancreatic Carcinoma: Results of a Pilot Study. Christian Bauer et al. in Cancer Immunology, Immunotherapy, Vol. 60, no. 8, pages 1097-1107; August 2011. www.springerlink.com/content/t56q865742198411
A new ally against cancer, by Eric von Hoff, Scientific American Israel, February-March 2012
and more on the site
2 תגובות
Curious
An interesting article, also humane.