Immunotherapy Research is Rebooting Seattle’s Biotech Sector

In the fall of 2013, researchers at Fred Hutchinson Cancer Research Center gathered at the bedside of a lymphoma patient about to undergo a new cancer treatment—the very first human in the treatment’s first human trial.

Dr. David Maloney, a Fred Hutch oncologist who specializes in developing immunotherapies for blood cancer patients, was there. It was his patient and his trial, testing the safety of immune T cells reprogrammed to recognize and destroy disease.
“We were kind of on pins and needles,” Maloney says. “The first infusions are always somewhat nerve-racking.”

The 30-minute procedure went smoothly, with Maloney and the team scrutinizing vital signs while he chatted with his patient, as he does at every infusion, he says, “so they’re not totally full of nerves.”

Days later, something remarkable happened. “Around day 14 or so after [the infusion of] T cells, his comments to me were that the lymph nodes in his neck felt like ice cubes melting,” Maloney says. “We knew the T cells were clearly doing something—in a very resistant tumor.”

For Maloney, it offered a fresh glimpse of the possible: a future in which cancer could be wiped out by something as simple to administer as an infusion of T cells, leaving healthy cells untouched so the patient would experience few side effects. And it’s no accident it happened in Seattle, where a historic effort to cure cancer and other challenging diseases that could change the course of medicine has been going on for years.

Immune system research, like Maloney’s, has always been an area of strength in Seattle but for many years, scientists had only a fuzzy idea of how the immune system functioned. Determined research and advances in sequencing technology recently enabled a clearer picture to emerge of what human bodies do to defend against invasion. Now, the immune system has become an area of huge potential, as researchers discover how to manipulate the complex system to combat disease more effectively.

As a result, the immunotherapy market is booming. Immunotherapy targets many diseases, but the cancer immunotherapy market alone is predicted to reach about $68 billion globally by 2018, according to BCC Research, a publisher of technology market research reports. Seattle has many of the necessary ingredients to become a major player, such as a vibrant research sector; strong collaborative relationships among scientists, entrepreneurs and pharmaceutical companies; and expertise in global health and data management, which is valuable in a changing health care landscape.

Seattle’s growing immunotherapy sector could also provide an important boost to local biotech, which took another hit this year when Amgen decided to shut down its operations here and lay off the 600 employees who remained from its acquisition of Immunex in 2002. Although the region has given many early-stage biotech companies and small startups promising beginnings, larger corporations that could serve as anchor tenants tend to move elsewhere.  

Multinationals and philanthropists are plowing money into research efforts that are bolstering Seattle’s already strong work in immunotherapy. In July, Celgene, a New Jersey biopharmaceutical company with $6.5 billion in revenues last year, announced it would open an Immuno-Oncology Center of Excellence based in Seattle. In September, the Danish company Novo Nordisk said it plans to add to its Seattle presence with an obesity research unit to focus on obesity and diabetes, an autoimmune disease. In April, the family of Amazon founder Jeff Bezos contributed $20 million to Fred Hutch to explore the potential of immunotherapies for treating lung, colon, breast and other common solid-tumor cancers.

Hans Bishop, CEO of Juno Therapeutics, which has received big investment for cancer-fighting immunotherapy treatments; photo credit: courtesy of Juno Therapeutics

But the biggest news may be from South Lake Union–based Juno Therapeutics. When the biotech start-up, which is developing a new treatment approach that harnesses the power of the body’s immune system to fight cancer, went public in December its listing price jumped 60 percent on the first day and gave the company a total market capitalization of 2.85 billion. That kind of money is rare for biotech startups anywhere in the world, let alone Seattle. And it speaks not only to Juno’s distinct offerings and its powerhouse staff, but also to the little recognized work in immunotherapy being done in places such as the University of Washington (UW), Fred Hutch, Seattle Children’s as well as other research institutions and private companies throughout the city that made Juno’s fundraising success possible.

Immunotherapy is being applied to a multitude of diseases, such as leukemia, melanoma, lupus and Graves’ disease. At the Benaroya Research Institute (BRI) at Virginia Mason, scientists are using immunotherapy to target type 1 diabetes, multiple sclerosis and rheumatoid arthritis. Dr. Gerald Nepom started the immunology program at BRI in 1985, and this year, the National Institutes of Health asked him to lead the Immune Tolerance Network, a global effort across 250 research sites to develop ways to “reprogram” the immune system, preventing the immune responses that lead to diseases such as asthma and diabetes while still maintaining the body’s ability to fight infection. For the next seven years, the network will be headquartered at BRI, which will receive $27 million annually in support funding. “[Immunotherapy] is becoming big science,” says Homer Lane, executive director at BRI. “It needs a lot of people to work together.”

But recent research suggests immunotherapy could play its biggest role in fighting cancer. Because it begins as mutations of our own cells, cancer often fools the immune system into remaining dormant as it grows. A research team at Fred Hutch made a major breakthrough when it pioneered bone marrow transplantation as a treatment for blood cancers in the 1970s.

In essence, a bone marrow transplant gives the patient an immune-system reboot. Hematopoietic stem cells live in bone marrow and are the foundation for white blood cells, a critical part of the body’s immune response. Chemotherapy and radiation destroy cancer cells, but also tend to kill many healthy cells and take a toll on bone marrow, so patients who have undergone high doses of both lose much of their ability to fight off infection and disease. By transplanting healthy bone marrow, scientists found that they could rebuild the immune response and allow patients to rebound more quickly from cancer treatment.

The early success with bone marrow transplantation won the Fred Hutch team, led by Dr. E. Donnall Thomas, a Nobel Prize in 1990. It also attracted other researchers interested in looking more deeply at—and eventually manipulating—the body’s immune response. Their primary target was T cells, a type of white blood cell that circulates in the blood and the lymph system and attacks disease-causing pathogens. The cells have a vast and complex system of triggers and responses.

Juno Therapeutics’ approach works by drawing blood from a patient, separating out the T cells and engineering them to provoke a particularly strong or targeted immune attack on cancer cells—a more nuanced approach than chemotherapy and radiation. In a recent study of 16 patients who had acute lymphoblastic leukemia with a typical median survival of less than six months, 14 achieved complete remission after being treated with engineered T cell therapy licensed to Juno.

Although that strategy came from Juno’s partner at Memorial Sloan Kettering Cancer Center in New York, Juno’s local partners at Seattle Children’s and Fred Hutch have also seen great success. “It’s truly incredible,” says Juno CEO Hans Bishop, who says he has seen patients recover after being treated with immunotherapy, when, previously, they had only a few weeks left to live. “In my career,” he explains, “I’ve never seen clinical results like this.”

Research by the UW’s Nora Disis has helped build one of the nation’s top cancer vaccine programs; photo credit: John Vicory

Over at the UW, Dr. Nora Disis, who works on immune-based cancer treatments and diagnostic tools, has helped to build one of the nation’s top cancer vaccine programs and works collaboratively with other local research institutions, such as Fred Hutch and Seattle Children’s. Bill Watt, who spent 15 years working in a lab environment before going into industry, is currently building a biotech startup called EpiThany, which will commercialize Disis’ work by developing vaccines that trigger the immune system to attack tumors.

“She’s just a colossus,” Watt says, describing Disis’ contribution to the field. EpiThany is putting three programs through clinical trials during the next year, and Watt is looking into collaborative relationships with other companies working in the realm of what are called “checkpoint inhibitors.” Sometimes, cancers send signals that put the brakes on the natural immune response. The inhibitors release the brakes again, making the enhancement provided by the vaccine far more effective.

The collaboration between Disis and Watt is a stellar example of the power of combining great research with entrepreneurial talent. Seattle has long had the research in spades. Now, more entrepreneurs are joining in. Case in point: Juno CEO Bishop, who has worked at Dendreon and Bayer HealthCare. Bob Nelsen, cofounder of ARCH Venture Partners and a member of Juno’s board, calls Bishop “the most qualified individual on the planet to run an immunotherapy startup.”

Nelsen may be biased, but he also speaks from experience. ARCH is the most active local investor in biotech startups, and Nelsen was an early champion of a different version of Juno’s technology, pioneered by a company called Xcyte. That startup amassed $150 million in financing only to sell its core technology for $5 million in 2005 after failing to get the treatment approved by the Food and Drug Administration.

Nelsen says his instincts told him not to invest in an industry in which he’d lost money before. But he was intrigued and eventually was won over by the strength of the science behind Juno and by Bishop’s experience at Dendreon, a company that had great early promise based on the immunotherapy-based drug protocol Provenge. The business rose to billions of dollars in valuation, but failed to deliver on its early promise, in part because of the $93,000 cost per patient of Dendreon’s treatment. Dendreon filed for bankruptcy protection in December. Nelsen says the lessons Bishop learned at Dendreon are now part of the library of knowledge that Juno can apply as it takes its treatment to patients. Bishop is taking the lesson to heart by focusing heavily on making Juno’s approach cost-efficient. “Process development is the biggest group at Juno,” he says.

There are some doubts about how far Seattle’s biotech companies can go in developing and marketing biotech treatments. “The latest stages of drug development and commercialization are not our [region’s] forte,” says Clay Siegall, CEO of Seattle Genetics. Chris Rivera, CEO of the Washington Biotechnology & Biomedical Association (WBBA), says he has seen more startups move toward partnerships or mergers and acquisitions in order to accomplish the final stages of getting a treatment to patients. He thinks that trend will continue.

But in the area of immunotherapy, Seattle has a broad range of strengths to draw from. One is strong support from local government. “The EDC is working with the city and state on an aggressive strategy to retain life science talent from Amgen and foster companies such as Juno,” says Suzanne Dale Estey, CEO of the Economic Development Council of Seattle and King County. Officials hope Juno will establish manufacturing facilities here and become another anchor tenant for the region’s biotech sector.

The promise of immunotherapy is drawing attention from many other companies. When Ron Myers left the Institute for Systems Biology in South Lake Union to become CEO of the UW spinoff Nexgenia in the University District, for example, he shifted the company’s direction to focus on one of the key challenges in commercializing immunotherapy: accurately and quickly sorting out the T cells from a patient’s blood so they can be activated and sent back into the patient’s body to do battle with cancer cells.

“Immunotherapy is revolutionary,” Myers says. “We are on the cusp of making it available to the masses. But the current state of manufacturing is far from optimized.” Oncothyreon, a biotech startup in Belltown, is taking an immunotherapy approach to developing vaccines that fight cancer.

Companies like Nexgenia and Oncothyreon can draw talent from among the alumni of Immunex, a biotech company that rose to prominence with Enbrel, a treatment for autoimmune disease. There is also a wealth of talent at the many research institutes in the area. And these researchers are accustomed to working in a research and biotech culture unlike many others.

“There’s a very collaborative spirit that seems to extend throughout the research institutions, the university, among some of the pharmaceutical firms who have a presence in town,” says BRI’s Lane. “That spirit has encouraged a lot of great success stories in the research field. It’s important in the way science is evolving, particularly the kind of research we’re doing.”

Rivera, of the WBBA, says Novo Nordisk, the European pharma giant that chose Seattle over Boston to build out its diabetes and obesity programs, called the city the only place where academia, nonprofits and industry are willing to sit down at a table together and talk about problem solving. “As far as industry getting things done,” Rivera says, “I think it’s a real asset that we have.”
“When you have a small community, there seems to be more dialogue,” notes Randall Schatzman, president and CEO of the 10-year-old Bothell firm Alder Biopharmaceuticals. “We’re cheering on everyone. Their success is our success.”
 
Bothell-based Seattle Genetics, the metro area’s true anchor tenant in the biotech sphere, offered Schatzman a conference room to use when he was starting Alder, and Paul Abrams, then the CEO of Ceptyr, also in Bothell, let the fledgling company use a bench in his lab for experiments. “We don’t have the concentration [of companies] of a Boston or a San Francisco,” Schatzman says, “but I think that’s a strength for us. I suspect that it would have been much more difficult for us as a startup to gain traction in one of those cities than it was here.”

Seattle has other advantages to draw from as it builds its immunotherapy sector. One is its large pool of global health experts. Rivera points out that the growing markets in the next two decades will not be North America and Europe, the traditional targets for health care startups, but China, Russia, Brazil and India. For help bringing new products to those markets, there’s no better resource than the global health field. Seattle has the largest concentration of global health organizations outside of Geneva, Switzerland, and those organizations not only have established relationships around the world, they also have years of experience in product distribution.

Take as an example the Infectious Disease Research Institute (IDRI). Recently honored by the Washington Global Health Alliance for its innovative approach and commitment to partnerships and training, IDRI was founded to bring products for treating infectious diseases to the developing world. Its scientists work on vaccines, diagnostic tools and therapeutic treatments. As part of its vaccine project, IDRI makes adjuvants, components added to vaccines that help stimulate the body’s immune response. One of its products is part of the core technology at Immune Design, another Seattle immunotherapy startup focusing on cancer treatment. “We’re truly world experts on these molecular structures,” says Erik Iverson, president of business and operations at IDRI.

Adjuvants are a useful tool in treating infectious disease, but they also have tremendous utility in treating allergies, cancer and HIV. This potential partly explains IDRI’s deep and sustained partnerships with many major players in the Seattle biotech world, including Seattle BioMed, Fred Hutch and the UW. The company also has a long-term partnership with Eli Lilly and Company, which donated to IDRI all the tuberculosis resources acquired from Lilly’s acquisition of Icos Corporation. “They effectively established our drug discovery program,” Iverson says.

Global health organizations are also experienced in keeping costs low, something that is more of a concern for health care companies since the introduction of the Affordable Care Act. In the past, treatments that made it through the FDA’s approval process were generally covered by most insurance, but now, that coverage is far from guaranteed, and there is a much closer eye on costs.
 
Another Seattle advantage is the strong presence of researchers making effective use of information technology. “Our biggest growth in membership is now digital health,” Rivera says. “You have Amazon, Microsoft, Tableau [Software]. Where else would you want to mix software and health care?”   

The UW has managed to attract some of the best minds in data science. Bioinformatics—a field that combines computer science, statistics, math and engineering to study and process biological data—is a growing division at many research institutes, including BRI and Seattle BioMed. Eastlake-based Adaptive Biotechnologies, which raised $105 million in funding earlier in 2014, has at its core advances in computational biology that allow the company to provide incredibly fast and thorough analysis of a patient’s immune system.

Seattle has most of the puzzle pieces in place to achieve success in immunotherapy. The unusual openness and collaborative spirit among researchers, small startups, large companies and industry players may help the region punch above its weight. And even if the Northwest never becomes another Boston or San Francisco, by building strength in important new areas such as immunotherapy, it could support a vibrant biotech economy.   

“For immune research, particularly cancer immunotherapy, there is no place in the world like Seattle,” Disis asserts. “If it can’t get solved here, it can’t get solved.”

Additional reporting by Andrea Detter/Fred Hutch News Service.