Immune Therapy Steps Up the Attack
Jennifer Couzin-Frankel
After years of trying, cancer researchers say they are finally having success enlisting the body's own defenses to destroy tumors.
Reinforcements! After the immune system tries and fails to fight tumors (first two panels), new therapies help these T cell knights get the job done.
CREDIT: RYAN SNOOK, WWW.RYANSNOOK.COM
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BETHESDA, MARYLAND—On a corner of Steven Rosenberg's desk rests a small, gold figurine representing Sisyphus, its arms straining to push a boulder forward. A gift from his wife when he joined the U.S. National Cancer Institute (NCI) here as chief of surgery back in 1974, it is uncannily apt: Rosenberg has spent 3 decades rolling metaphorical boulders uphill, only to see them tumble back down again.
Rosenberg's specialty is immunotherapy; he tries to harness a patient's own immune system to fight cancer. He and others have seen remnants of immune system attacks on tumors, but the cancer recovers and takes off. Efforts to lend the immune system a hand have raised hopes, leading to large clinical trials of cancer vaccines. But all have flopped. And year after year, nearly all of Rosenberg's patients, recipients of radical experimental treatments, succumbed to their cancer.
Nearly all, that is, until recently.
Slowly, new immune-based therapies are registering successes. In some people riddled with the aggressive skin cancer melanoma, immunotherapy has not only eliminated disease but also kept it at bay for years. Such outcomes are virtually unheard of in patients with metastatic disease that has spread through the body. Last month, NCI awarded $14 million to the Fred Hutchinson Cancer Research Center in Seattle, Washington, so it could launch a new national network of immunotherapy clinical trials.
From a patient's perspective, the achievements are still tenuous. Some individuals respond dramatically. But only a fraction are treated successfully—about 15% at most, though some small trials have hints of higher numbers. What excites immunotherapists is that this modest group of responders—the "tail end of the curve"—keeps showing up in recent studies. This year, it appeared in trials of two antibodies used against several different cancers, and in data from Rosenberg's cell therapy recently published or presented at meetings. With more tinkering, cancer specialists hope to shift additional patients into the responder category and devise more powerful combination treatments. Accustomed to disappointment, they have rarely been so confident.
At the same time, their successes are raising deep questions about where cancer therapy is headed. Integrating immunotherapy into clinical care will pose challenges of its own. Patients may take months to respond, making it difficult to assess whether treatment is helping. Furthermore, some treatments are highly personalized and impossible to administer outside of specialized settings. This makes them extraordinarily expensive. Many specialists wonder whether they can really become part of standard cancer care.
Rosenberg is a believer. "The goal right now is to find things that work," he says. "When you find things that work, industry finds ways to make it happen."
Rocky start
One patient has never left Rosenberg's thoughts. As a junior resident in a Boston hospital in 1968, Rosenberg met James DeAngelo, then in his 60s, who had been admitted for gallbladder surgery. Twelve years earlier, DeAngelo had developed a stomach cancer that spread to his liver and was sent home to die. Instead, his cancer spontaneously regressed without treatment—"one of the rarest events in all of medicine," Rosenberg says now.
One of Rosenberg's first surgery cases became part of an experiment. At the time, Rosenberg recalls, "there was someone else in the hospital who had gastric cancer" and whose blood type matched DeAngelo's. Following the wild theory that something in DeAngelo's blood could help this desperately ill man, Rosenberg transfused blood from DeAngelo into the second patient. Nothing happened, and that man later died of his cancer.
But Rosenberg couldn't shake the memory of that gallbladder surgery, where he ran his hands across DeAngelo's liver and found no hint of disease. Had DeAngelo's body fought off cancer on its own?
In some ways, the notion didn't make sense. Cancer cells are a patient's own, so why would the body perceive them as invaders? The answers are now clear. Among them: Tumor cells are genetically unstable and pile on new mutations that render them distinct from the host. In 2007, oncologist Bert Vogelstein of Johns Hopkins University in Baltimore, Maryland, and his colleagues reported in Science that breast and colon cancers can harbor hundreds of gene mutations—an "unexpectedly high number," says Suzanne Topalian, a Johns Hopkins melanoma specialist who was not involved in the work. And those mutations "should be recognized by the immune system," she says. Studies have confirmed it: Tumor cells often display antigens not found elsewhere in the body that prompt immune reactions.
Immunotherapists targeted melanoma because primary melanoma tumors—as opposed to metastatic ones—are among the few that can spontaneously disappear. Doctors also identified antibodies to melanoma in the blood of patients and a higher incidence of the cancer in those who'd received organ transplants and had suppressed immunity. All of these clues suggested that the immune system engaged in an elaborate dance with the disease.
Given that roughly 8 million people around the world will die of cancer this year, it's clear that the immune system alone is no match for cancer's wiles. Robert Schreiber of Washington University School of Medicine in St. Louis, Missouri, advanced a framework in 2001 that's often cited to explain why. Schreiber argued that the immune system does go after the tumor initially: He called it the elimination phase. This may destroy many cancers before they're detected. But he argued that other tumors develop an immunosuppressive barrier, expressing proteins on their surface that dampen immune attacks. In this equilibrium phase, the tumor and the person with cancer coexist. At some point, the cancer slips into the escape phase, where the balance tips in its favor.
In the past 2 decades, dozens of therapies have tried to stimulate the immune system against cancer, including about 20 vaccines that reached mid- and late-stage clinical trials. "We've been excited by every single one of these," says Mario Sznol, an oncologist at the Yale School of Medicine who focuses on melanoma and kidney cancer. But, he concedes, "for the most part, none of those things really did much."
Because tumors evolve to prevent the body from recognizing them as foreign, vaccines need to trigger a massive immune response. Most cancer vaccines just haven't been potent enough, says Jeffrey Weber, a melanoma specialist at the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida: "We've been giving very wimpy immunizations, in my view." They may have been ineffective for another reason: Researchers had only a rudimentary understanding of how the immune system and tumors interact. Slowly, that is changing.
Antibody breakthroughs
"The science is now guiding the medicine," says Jedd Wolchok, a melanoma specialist at Memorial Sloan-Kettering Cancer Center in New York City. "The paths that we are taking are built upon a much more solid understanding of what is going on molecularly."
Empowering T cells is a key part of the new strategy. One breakthrough came in 1996, when Wolchok's colleague James Allison reported in Science that a protein called CTLA-4 makes T cells less active (22 March 1996, p. 1734). In mice, Allison found that blocking CTLA-4 with an antibody killed tumors. A biotechnology company called Medarex picked up anti-CTLA-4, which now goes by the generic name ipilimumab, in hopes of turning it into a cancer therapy. Wolchok, Rosenberg, and others began testing it in people.
In a small number of patients, the results were dramatic. "I do remember those early days; we were looking at CT scans and saying, ‘Oh my goodness, this thing's really working,’" says Topalian. In the summer of 2009, the pharmaceutical giant Bristol-Myers Squibb purchased Medarex for $2.4 billion, gaining rights to both antibodies.
In August 2010, the company and its academic collaborators reported on the phase III results of an ipilimumab trial with 676 melanoma patients. For the first time ever, a randomized trial found that people with stage 4 melanoma benefited from a new treatment. The advantage was modest: Treated patients survived 10 months, on average, compared with 6.4 months for controls. "What is exciting is when you look at the tail of the curve," says Allison. "Very few patients survive more than 2 years with metastatic melanoma," and in this trial, just under a quarter of those treated did. Many still have tumors, however, but their disease is stable and they don't need treatment, says Allison. Only three out of the 540 who received the therapy were free of cancer altogether.
Just as chemotherapy comes with risks, so does ipilimumab. Side effects included severe diarrhea, colitis, and endocrine disruption; 14 patients died from the treatment. Still, researchers believe that ipilimumab will gain approval from the U.S. Food and Drug Administration (FDA) in the coming months.
Summit. Steven Rosenberg says his 30-year push for an immune-based assault on melanoma is working at last.
CREDIT: RHODA BAER/NATIONAL CANCER INSTITUTE
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Medarex had also been working on another naturally occurring protein called PD-1 that dampens immune responses. Whereas mice without CTLA-4 die of immune defects, those without PD-1 are healthier, suggesting that an antibody against PD-1 could have fewer side effects.
The response rate for anti-PD-1 looks hopeful. Results from a small trial published in July in the Journal of Clinical Oncology and additional data presented at a cancer meeting in June suggest that about one-third of melanoma and kidney cancer patients responded—that is, their tumors shrank. "The most amazing thing of all," says Drew Pardoll of Johns Hopkins, who has been involved in the development of anti-PD-1, is that up to 3 years after treatment, "not a single responder has yet relapsed. ... That's eye-popping." Many of them still harbor tumors, but "they're just sitting there" and not growing, says Pardoll.
Both antibodies are being tested in other cancers. Responses to ipilimumab have shown up in ovarian, prostate, and lung cancer, in addition to melanoma, says Allison. In theory, if a patient's T cells are reacting to tumor antigens, this approach "can be used for any kind of cancer."
Narrow success
Antibodies like ipilimumab are valuable, Rosenberg says, but in his mind, they're not nearly enough. If the cancer doesn't completely disappear, "everybody dies" eventually, he says. Rosenberg wants a cure, and he is willing to go to great lengths to get it.
He's testing a different approach at the National Institutes of Health (NIH) Clinical Center here, which draws people from all over who are running out of options and treats them free of charge. Rosenberg estimates his budget for immunotherapy at about $3 million a year, far higher than virtually anywhere else.
On this day he drops in on a cheerful woman in her mid-40s with reddish-brown hair and chunky black glasses. She will be the first person to receive Rosenberg's immunotherapy for colorectal cancer. If it fails, he guesses she has between 4 and 6 months to live.
Unlike antibody therapy, which is administered intravenously in an outpatient setting, Rosenberg's method requires hospitalization and a research clinic, at least for now. He focuses on finding T cells activated to attack cancer, usually in tumor tissue. His goal is to extract these T cells, grow them into the tens of billions outside the body over several weeks, and give them back. To make this work, Rosenberg discovered several years ago that he first needs to destroy a patient's existing immune cells with high doses of chemotherapy and sometimes total-body irradiation.
Rosenberg's approach is not an option for many patients. T cells can't be harvested from those with inaccessible tumors, about one-fifth of melanoma patients. For another fifth, the cells don't grow well outside the body. Many can't wait the month it takes to expand cells in the lab. And the pretreatment chemotherapy, as well as a drug given during treatment, is so toxic that most people over 70 can't tolerate it.
But for those lucky enough to have that precious bag of T cells returned to them, the likelihood of success is impressive. Out of 93 patients with metastatic melanoma who have received the treatment and been followed long-term, 20 saw their cancer disappear completely. Nineteen have remained cancer-free for 3 to 8 years. In another 32, tumors shrank. Nearly all of these patients had failed every available therapy, including, in many cases, ipilimumab.
In his office, Rosenberg clicks through a series of CT scans on his computer screen from one of his success stories, a police officer coming in for a follow-up visit. Like most of Rosenberg's patients, the policeman had metastatic melanoma. Although suffering long-term effects from radiation he received when Rosenberg treated him, he's been free of cancer since T-cell therapy 4 years ago.
Rosenberg is now trying to get around one big limitation of his strategy: the need for tumor tissue as a source of T cells. He's experimenting with removing T cells directly from the blood of patients and genetically engineering them to recognize antigens on tumors. This would potentially open up the therapy to people with all sorts of cancers, especially those with hard-to-reach tumors that can't be surgically removed for the T-cell hunt. Rosenberg is also beginning to extend his therapy to lymphoma and sarcoma as well as colon cancer. So far, the few patients treated are doing well.
Several large academic medical centers in Seattle, Houston, and elsewhere have also been working on refining the therapy, called adoptive T cell transfer (ACT). All report roughly comparable success rates, but none is doing as much as Rosenberg at NCI—largely, they say, because of the cost.
CREDIT: (SOURCE) BRISTOL-MYERS SQUIBB, GLAXOSMITHKLINE, AND STEVEN ROSENBERG
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Although the results are compelling, ACT "is 100 times as hard to export, to do in a reproducible fashion, and it's also a lot more expensive than" antibodies, says Pardoll. "Companies essentially have no interest in it. It really right now is a purely academic exercise."
ACT has taught us a great deal, says Wolchok at Sloan-Kettering—for example, that people with heavy cancer burdens can be helped just by expanding and reintroducing their T cells. But ACT faces daunting hurdles in "being able to produce the cell product for every patient who needs it," he says. Even in Rosenberg's lab, the cells don't always grow, says Wolchok, who has referred patients to the program. Sznol at Yale has looked into setting up an ACT program there, but the logistics have made it too difficult to pull off yet.
Although Rosenberg agrees that companies haven't invested in ACT, he is frustrated by those who critique its practicality. He has a lab member working full-time with NIH's blood bank to determine whether it can grow patients' cells more efficiently. NCI recently began a randomized clinical trial of ACT in melanoma. The hope is that if ACT proves superior, payers might cover its cost, which depends on the protocol but can exceed $100,000 per patient.
Even doubters recognize that what's dismissed as impossible in medicine is always changing. "Monoclonal antibodies had the same stones thrown at them 20 years ago," with everyone questioning their feasibility, says Wolchok. With ACT, "it may just be time for the technology to catch up with the need."
After much hesitation, pharmaceutical companies have expressed growing enthusiasm for cancer immunotherapy. In April, FDA approved the first cancer vaccine, called Provenge, for metastatic prostate cancer, made by the company Dendreon in Seattle. Treatment consists of three infusions for a total cost of $93,000. Many oncologists are underwhelmed by its effectiveness. The vaccine extends survival by 4 months; it does not stop cancer. But just the fact that Dendreon pushed ahead with the vaccine, which is custom-made for every patient, is heartening to some immunotherapists.
Bristol-Myers Squibb has its antibodies—ipilimumab and anti-PD-1—while another pharma giant, GlaxoSmithKline (GSK), is running several large trials of a new cancer vaccine for lung cancer and melanoma. Unlike Provenge, the GSK vaccine is an off-the-shelf mix. It includes an antigen, MAGEA3, that commonly appears on cancer cells, and an adjuvant to boost immune reactions; introduced together, these aim to stimulate the immune system to go after cells expressing MAGE-A3. GSK is trying to use gene profiling of tumors to carefully pick patients most likely to respond. "We do not want to have the clinical efficacy diluted because we don't select the right patients," says Vincent Brichard, head of immunotherapeutics at GSK Biologics in Rixensart, Belgium. "This could explain why previous trials have failed."
Skill and subtlety
As immunotherapy edges into the clinic, it's likely to challenge oncologists' expertise. When chemotherapy works, it works quickly; immunotherapy is very different. "You might not see responses right away, and they may get worse before they get better," says Cassian Yee of the Fred Hutchinson Cancer Research Center. "It does take a little bit of insight for the person managing the patient to say, ‘OK, your tumor's only grown by 10%, 20%—we think that you should continue" on ipilimumab.
No one yet knows why tumors might grow before they dissipate. Indeed, there's still much that remains a mystery about how antibodies and ACT behave in the body, how to predict who they'll help, and how to make them more effective.
A subset of patients might have what Thomas Gajewski of the University of Chicago in Illinois calls the "inflamed phenotype": They are capable of "making some smoldering immune response against their tumor that you can tip over" in their favor, shrinking the cancer or erasing it altogether. Gajewski estimates that at least 30% of patients fall into this category. He's looking for ways to coax the other 70% to respond: "How do you make the noninflamed tumors inflamed?" he wonders.
Most cancer specialists believe the solution will come from combination therapies. Like Gajewski, Allison theorizes that immunotherapy is most effective when an immune response is already under way, with T cells activated and tumor cells dying. One way to tip more patients into this category might be by supplementing immunotherapy with direct killing of tumor cells. Bristol-Myers Squibb is running a large prostate cancer trial that combines ipilimumab with a single dose of radiation to do just that. In theory, the antibody might also enhance the potency of T cells given in ACT, says Yee.
Which treatments will go mainstream? "Everybody's goals are the same: Let's try to cure cancer patients," says Rosenberg. But is it reasonable to set up expensive cell growth facilities, as some want NCI to do, especially if they'll help only a subset of patients? And who will pay? With immunotherapy, no matter which approach you take, says Yee, "you're going to start off with high expenses." The hope is that long term, the payoff will be worth it.
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