Argos Therapeutics - How Ralph Steinman Raced to Develop a Cancer Vaccine – And Save His Life
When Ralph M. Steinman developed pancreatic cancer, he put his own theories about cancer and the immune system to the test. They kept him alive longer than expected—but three days short of learning he had won the Nobel Prize
Peering through a microscope at a plate of cells one day, Ralph M. Steinman spied something no one had ever seen before. It was the early 1970s, and he was a researcher at the Rockefeller University on Manhattan’s Upper East Side. At the time, scientists were still piecing together the basic building blocks of the immune system. They had figured out that there are B cells, white blood cells that help to identify foreign invaders, and T cells, another type of white blood cell that attacks those invaders. What puzzled them, however, was what triggered those T cells and B cells to go to work in the first place. Steinman glimpsed what he thought might be the missing piece: strange, spindly-armed cells unlike any he had ever noticed.
His intuition turned out to be correct. These dendritic cells, as Steinman named them, are now thought to play a crucial role in detecting invaders in the body and initiating an immune response against them. They snag interlopers with their arms, ingest them and carry them back to other types of immune cells—in effect, “teaching” them what to attack. It was a landmark discovery that explained in unprecedented detail how vaccines worked, and it propelled Steinman into the top tiers of his profession.
In many ways, Steinman’s story is typical: brilliant scientist makes major discovery that inspires a new generation of researchers.Indeed, his insight was remarkable for its implications, both for science and for him personally.
Over the years Steinman came to believe that dendritic cells were a crucial weapon for tackling some of the most loathed diseases, from cancer to HIV. He and his global network of colleagues seemed to be well on the way to proving him correct when Steinman’s story took an unusual turn.
In 2007 he was diagnosed with pancreatic cancer, an unforgiving disease that kills four out of five patients within a year. In the end, the cells he discovered at the start of his career, and the friends he made along the way, would not only help him fight his cancer but would extend his life just long enough for him to earn the Nobel Prize. He died this past September, three days before a flashing light on his cell phone alerted his family that he had won.
A Prepared Mind
Steinman did not encounter serious biology until he arrived as a student at McGill University. As soon as he did, though, he was hooked,and it was his fascination with the minuscule world of the immune cell that would bring him to the lab of Zanvil A. Cohn at Rockefeller. In his office Steinman would later display a quote from the famous 19th-century microbiologist and vaccinologist Louis Pasteur: Le hazard ne favorise que les esprits préparés, which is often translated as “Chance favors the prepared mind.” Says Sarah Schlesinger, a longtime colleague and friend of Steinman, “Ralph was exceedingly well prepared, so he was poised to make a discovery. But with that said, he intuited that these were important,” she says of the cells. It was that intuition and a confidence in observation that enabled him to make his seminal discovery—and eventually win the admiration of colleagues.
After he first spotted dendritic cells, Steinman spent the next two decades convincing the scientific community of their significance, defining how they worked and how researchers could work with them. “He fought—there’s really no other word for it—to convince people that they were a distinct entity,” says Schlesinger, who came to work at Steinman’s lab in 1977, when she was still in high school. Even then, she says, people in the same lab were not convinced that these dendritic cells existed because they were difficult to enrich into larger batches. At the time, Steinman was still working at the bench, and Schlesinger recalls sitting with him at a two-headed microscope, examining the cells. “He just loved to look at them,” she says, smiling at the memory. “There was such a joy in all of the little discoveries that he made.”
By the 1980s Steinman, who had trained as a physician, started to look for ways his dendritic cell discovery could be applied more directly to help people. Over the next few decades, as the cells became more widely accepted, his lab expanded its focus to include research into dendritic cell–based vaccines for HIV and tuberculosis, as well as research into cancer treatment. For illnesses such as influenza or smallpox that could already be prevented with vaccines, those who survive natural exposure may develop a lifelong immunity. HIV, TB and cancer presented a greater challenge because they seemed to be better at overcoming the immune system—even, in the case of HIV, hijacking dendritic cells to do its dirty work. “Ralph would say, ‘We have to be smarter than nature,’” Schlesinger says. That meant helping the dendritic cells by giving them more targeted information about the virus or tumor against which the immune system needed to form an attack.
In the 1990s, working with Madhav Dhodapkar, now at Yale University, and Nina Bhardwaj, now at New York University, Steinman created a process for extracting dendritic cells from the blood and priming them with antigens—telltale protein fragments—from infections, such as influenza and tetanus, and then placing them back in the body to create a stronger immunity. This technology served as the basis for a prostate cancer vaccine called Provenge that was approved in 2010 and has been shown to extend the life of terminally ill patients—if only by a few months.
The Final Experiment
In early 2007 Steinman was away in Colorado at a scientific meeting, a trip that he had turned into a family ski vacation, when he and his twin daughters all had what seemed like a stomach bug. His daughters recovered quickly, but his illness lingered. Soon after he returned home, he developed jaundice. In the third week of March he went in for a CT scan, and radiologists found a tumor in his pancreas. By then, it had already spread to his lymph nodes. He knew his odds of survival were slim: about 80 percent of pancreatic cancer patients die within a year.
“When he first told us, he said, ‘Do not Google this—just listen to me,’” his daughter Alexis recalls. She felt like someone had punched her. “He really expressed to the family that while it was a very drastic disease, he was in a very good position,” she says. Unlike the average cancer patient, Steinman had access to many of the top immunologists and oncologists on the planet—and, perhaps even more important, to their most promising therapies.
When Schlesinger heard the news, she was devastated. And she quickly rallied to her mentor’s side. She, Steinman and their close Rockefeller colleague Michel Nussenzweig began making phone calls, sharing the news with colleagues across the globe. Steinman was convinced that the surest way to be cured of any tumor was to develop immunity against it through his own dendritic cells. They had a limited amount of time to prove him right.
One of the early calls Steinman made after his diagnosis was to his longtime collaborator Jacques Banchereau, who now directs the Baylor Institute for Immunology Research in Dallas. Banchereau then picked up the phone to call Baylor researcher Anna Karolina Palucka, who had known Steinman since the 1990s. Although she had an experimental vaccine in the works that she thought could help Steinman, she struggled with the personal challenge of trying “to compartmentalize the friend, the patient and scientist.”
For her part, Schlesinger called Charles Nicolette, a friend and collaborator of many years and chief scientific officer of Argos Therapeutics, an RNA-based drug company in Durham, N.C., that Steinman had co-founded. Nicolette, reeling from the news, mobilized his own colleagues within minutes of hanging up the phone.
Nicolette’s group had developed a dendritic cell vaccine that was in a phase II (intermediate-stage) clinical trial to treat advanced kidney cancer. Argos’s therapy endeavors to enlist a patient’s own dendritic cells against a cancer by exposing them to genetic material, from the tumor, which induces them to rally T cells to mount a proper attack.
Steinman was scheduled to have part of his pancreas removed the first week of April 2007—a surgery known as a Whipple procedure, which is part of more traditional treatment for his prognosis. Nicolette would need part of that tumor to draw up his vaccine, which left him just days to get the U.S. Food and Drug Administration to approve Steinman’s entry into his trial, permission the team was able to secure just in time.
With the tumor cells secured and while the Argos treatment was brewing, a process that would take months, Steinman started in on other therapies. Soon after his surgery, he went on standard Gemcitibine-based chemotherapy, and then, in the late summer, he enrolled in a trial of GVAX, a dendritic cell–based vaccine that was being tested to treat pancreatic cancer. Co-developed by Elizabeth Jaffee of Johns Hopkins University and administered at the Dana-Farber/Harvard Cancer Center, the vaccine uses a generic tumor antigen, as the Provenge prostate cancer vaccine does. In an earlier phase II trial, pancreatic cancer patients who had received the vaccine lived an average of four months longer than those who had not, and some ended up living for years. So for two months, starting in the late summer, Schlesinger traveled with him to Boston almost every week. “I remember walking in Boston on a day like this,” she says, looking out of her corner office window into the clear, paling blue October afternoon sky, “thinking, ‘He’s not going to see another fall,’ and I was so sad.”
But fall came and went, and Steinman remained in relatively good health. In September 2007 he received the Albert Lasker Award for Basic Medical Research, considered by many to be a precursor to the Nobel, and he sat for a series of video interviews. In them, he elaborated on the promise of dendritic cells to fight cancer, noting that an immune attack is highly directed, highly specific and, unlike chemotherapy, nontoxic. “I think this provides the potential for a whole new type of therapy in cancer,” he said. “But we need research and patience to discover the rules, to discover the principles.”
At times, Steinman showed more patience than his colleagues would have liked. He had initially argued for a very slow course of treatment for himself so that his team could monitor his immune response after each therapy before beginning the next. But Schlesinger and Nussenzweig eventually convinced him that they simply did not have the time. If he died, the experiment and data collection were over.
By November 2007 the Argos vaccine, made by infusing cells taken from Steinman’s blood with genetic material extracted from his tumor, was ready and waiting. Steinman had just finished with a chemo treatment, and he enrolled in Argos’s renal cell carcinoma trial under a single-patient study protocol.
In early 2008 Steinman followed up with Palucka’s vaccine, which was being developed for melanoma. It incorporated a selection of tumor-specific peptides (protein fragments), so she suspected it could be repurposed to target Steinman’s cancer by using peptides from his tumor in place of antigens from melanoma.
Other offers for experimental treatments poured in from all over the world. “Everybody who could brought the best they could,” Palucka says. Steinman’s decades of collegial work had united the field, and now that network of scientists turned to help one of their own. “People think of science as a solitary process. In fact, it’s an extremely social process,” Schlesinger says. The “social nature of our work facilitated the forthcoming of these tremendous intellectual resources.”
In addition to standard treatment, Steinman ended up enrolled—under a special patient provision—in four ongoing clinical trials of various dendritic cell–based cancer treatments, most of which were not even being tested for pancreatic cancer, along with several other experimental immunotherapy and chemo treatments. Schlesinger, a member of the Rockefeller Institutional Review Board (IRB), steered his treatment through all the necessary IRB and FDA channels, making sure the standard protocols were followed. She also personally gave Steinman his vaccines whenever they could be administered at Rockefeller.
Steinman ran his own grand experiment like he ran others in the lab—always carefully collecting data, evaluating the evidence and doling out instructions. Schlesinger still has e-mail chains from the period, Steinman’s messages coming back in all capital letters per his style. He kept particularly close tabs on how his own body was responding to treatment. In 2008, during his time on Palucka’s therapy, she came for a visit to New York City. After Schlesinger had given Steinman his dose of the vaccine, the three of them went out to dinner. On finishing their meal, Steinman insisted they stop by Palucka’s hotel so that he could show them the welt developing on his leg around the injection site. “He was so enthused about it,” Schlesinger says. “He said, ‘Those are T cells’”—indicating that his body was having an immune response to the vaccine—“‘that’s great!’”
The local swelling showed that Steinman’s body was reacting to the vaccine, although, Palucka says, she cannot be certain it was tumorspecific T cells that had been mobilized. As she points out, all vaccines work through dendritic cells, but the difference with her therapy and the others that Steinman tried was that rather than leaving exposure up to chance, researchers manipulated the dendritic cells outside of the body to improve the odds they would train T cells to attack the tumor. When Schlesinger was not on hand to see the evidence for herself, she says, “he would send me these descriptions of the vaccination sites with great enthusiasm,” including information about the appearance and size of the sites—and even how each one felt.
His tumor marker, the level of a protein that indicates the progress of a cancer (which fluctuated throughout the course of his treatment), became a barometer for his attitude. The second time the marker went down, he sent an e-mail out with the subject line “We’ve repeated the experiment,” the glee of which was apparent to those who knew his joy in a scientific triumph.
But the good news that satisfied Steinman the patient was never good enough to satisfy Steinman the scientist. The knowledge that his one-person experiment was hardly a scientific one frustrated him to no end. With the experimental treatments administered so close to one another—and interspersed with traditional chemotherapy—it was impossible to know what sent his tumor biomarker downward.
Nevertheless, Steinman generated some interesting data points along the way. During one of Palucka’s immune-monitoring tests during his treatment, she found that some 8 percent of cells known as CD8 T cells (also called killer T cells) were specifically targeted to his tumor. That might not sound like a lot, but given all the potential pathogens that the body can encounter and mount an attack against, 8 percent “is a huge number,” Schlesinger says. “So something immunized him—or some combination of things immunized him.”
A Death, Days Too Soon
Steinman and his wife, Claudia, traveled to Italy to celebrate their 40th wedding anniversary in June 2011—just two months after what he referred to as his fourth “Whipple-versary,” in honor of his April 2007 surgery. Already he had far surpassed the average survival of a person with his type of cancer.
In mid-September 2011 Steinman was still working at the lab, and arrangements had been made for him to restart the Argos treatment. Then Steinman fell ill with pneumonia. “When he was admitted to the hospital, he said, ‘I might not make it out of here,’” Alexis recalls. But after her father’s four and a half years of good health, she found it hard to believe she would have only days left with him. He was still reviewing data from Rockefeller as late as September 24. On Friday, September 30, he died at the age of 68 from respiratory failure caused by pneumonia, which his cancer-weakened body could no longer fend off.
His family struggled with how to even begin to tell his vast network of friends and colleagues around the globe. They planned to visit his old lab—where he had been working until so recently—to tell those there on Monday, October 3. But early that morning, before any of them were awake, Stockholm called. Steinman’s BlackBerry, on silent, was with his wife. In a fitful, early-morning sleep, she glanced over to see a new-message light blinking. Just then an e-mail popped up, politely informing Steinman that he had won the 2011 Nobel Prize in Physiology or Medicine.
The first response was that “we all collectively screamed the ‘f’ word,” Alexis says. Her next thought was, “Let’s go wake up Dad.”
But for the rest of the world, nothing about the Nobel committee’s announcement seemed amiss—articles were written, statements were issued about Steinman and the two other recipients, Bruce Beutler of the Scripps Research Institute and Jules Hoffmann of the French National Center for Scientific Research—until a few hours later, when news of Steinman’s death surfaced. The prize rules state that it cannot be given posthumously, but if a laureate dies between the October announcement and the award ceremony in December, he or she can remain on the list. This odd timing threw the committee into a closely followed deliberation before it announced, late in the day, that he would remain a prize recipient.
Just days after Steinman’s Nobel was announced and news of his death hit the media, pancreatic cancer also claimed the life of Apple co-founder and CEO Steve Jobs. Jobs, ill with a rare, slower-growing form of the disease—a neuroendocrine tumor—lived for eight years after his diagnosis, more of an average survival time for a patient with his form of the disease. Steinman’s survival, though, far surpassed what was expected. “There’s no question something extended his life,” Schlesinger says.
Now researchers are working to figure out what it was. In early 2012 Baylor will be dedicating the Ralph Steinman Center for Cancer Vaccines, and Palucka is developing a clinical trial to treat pancreatic cancer patients with the same vaccine that she helped create for Steinman. At Argos, Nicolette is pursuing their kidney cancer vaccine full steam ahead: “There’s a sense of duty to Ralph to see this through.” This month they plan to launch a phase III clinical trial of the renal cancer vaccine Steinman tried.
For her part, Schlesinger believes her colleagues’ interventions made a contribution in the end. “The scientific message is: immunity makes a difference,” she says. But the final lesson is one Steinman liked to preach. “He used to tell people, ‘There are so many other things left to discover,’” she recalls. “And there are.”