Cancer Cure Inc.

Many of the biggest achievements in this city fly under the radar because Seattle is a casual place. Nobody brags. Nobody struts. Yet a historic effort to cure cancer and other challenging diseases that could change the course of medicine has been going on for years right under our noses.

Juno Therapeutics recently launched a central part of that effort into the spotlight. The biotech startup raised more than $310 million in less than 12 months to fund a new treatment approach that harnesses the power of the bodys immune system to fight cancer. That kind of money is rare for biotech startups anywhere in the world, let alone Seattle. And it speaks not only to Junos distinct offerings and its powerhouse staff, but also to the little recognized work on immunology being done in places like the University of Washington, the Fred Hutchinson Cancer Research Center, Seattle Childrens as well as other research institutions and private companies throughout the city that made Junos fundraising success possible.

Juno Therapeutics scientific cofounders. From left, Doctors Michel Sadelain, Michael Jensen, Isabelle Riviere, Phil Greenberg, Stan Riddell and Renier Brentjens

Immune system research 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 that is valuable in a changing health care landscape.

Seattles growing strength in immunotherapy could also provide an important boost to its struggling biotech sector, 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.

Multinationals and philanthropists are plowing money into research efforts that are bolstering Seattles 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 the Novo Nordisk 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.

While immunotherapy is being applied to a multitude of diseases, recent research suggests it could play its biggest role in fighting cancer. Cancer is a tricky disease. Because it begins as mutations of our own cells, it 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 bodys immune response. Chemotherapy and radiation destroy cancer cells, but also take a toll on the bone marrow, so patients who have undergone high doses of both lose much of their ability to fight off infection or 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 bodys 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, which also tend to kill many healthy cells. In a recent study of 16 patients who had acute lymphoblastic leukemia with a typical median survival of less than 6 months, 14 achieved complete remission after being treated with engineered T-cell therapy licensed to Juno.

Although that technology came from Junos partner at the Memorial Sloan-Kettering Cancer Center in New York, Junos local partners at Seattle Childrens and Fred Hutch have also seen great success. Its 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, Ive never seen clinical results like this.

The potential for immunotherapy to provide a cure extends far beyond cancer. 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 like asthma and diabetes while still maintaining the bodys 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. [Immunology] is becoming big science, says Homer Lane, executive director at BRI. It needs a lot of people to work together.

Key Investigator. Dr. Nora Disis, a UW professor, focuses her research on developing vaccine and cellular therapies for breast and ovarian cancer.

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

Shes 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 kicking 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 Junos 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 Junos technology pioneered by a company called Xcyte. The 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 where hed lost money before. But he was intrigued and eventually won over by the strength of the science behind Juno and by Bishops 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 Dendreons treatment. Nelsen says the lessons Bishop learned at Dendreon are now part of the library of knowledge that Juno can apply as it takes its technology to patients. Bishop is taking the lesson to heart by focusing heavily on making Junos technology cost efficient. Process development is the biggest group at Juno, he says.

There are some doubts about how far Seattles biotech companies can go in developing and marketing biotech treatments. The latest stages of drug development and commercialization are not our [regions] forte, says Clay Siegall, CEO of Seattle Genetics. Chris Rivera, CEO of the Washington Biotechnical and 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 regions biotech sector.

The promise of immunotherapy is drawing attention from many other companies. When Ron Myers left the Institute for Systems Biology to become CEO of the UW spinoff Nexgenia, for example, he shifted the companys direction to focus on one of the key challenges in commercializing immunotherapy: accurately and quickly sorting out the T cells from a patients blood so they can be activated and sent back into the patients 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, another Seattle-based biotech, 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.

Theres 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 BRIs Lane. That spirit has encouraged a lot of great success stories in the research field. Its important in the way science is evolving, particularly the kind of research were 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 were willing to sit down at a table together and talk about problem solving. As far as industry getting things done, Rivera says, I think its 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. Were cheering on everyone. Their success is our success.

Seattle genetics, the city 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, let the fledgling company use a bench in his lab for experiments. We dont have the concentration [of companies] of a Boston or a San Francisco, Schatzman says, but I think thats 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, theres no better resource than the global health field. Seattle has the largest concentration of global health organizations outside of Geneva, 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 bodys immune response. One of its products is part of the core technology at Immune Design, another Seattle immunotherapy startup focusing on cancer treatment. Were 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 IDRIs 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, which donated to IDRI all the tuberculosis resources acquired from Lillys 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 FDAs approval process were generally covered by most insurance, but now that coverage is far from guaranteed and there is a much closer eye on product costs. In July, Congress opened an investigation into Gilead Sciences treatment for hepatitis C, which costs roughly $1,000 per pill in the United States, or $84,000 for a 12-week course of treatment.

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 University of Washington has also 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. 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 patients 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 immunology, it could support a vibrant biotech economy.

For immune research, particularly cancer immunotherapy, there is no place in the world like Seattle, Disis asserts. You have all these number one things in a small location in an area that encourages collaboration and entrepreneurship. If it cant get solved here, it cant get solved.

What Is Immunotherapy?

Immunotherapy treats disease by manipulating the immune response. The immune system is one of the most complex systems in the body, second only to the nervous system. It is made up of different groups of cells and proteins distributed throughout the body, working together to prevent and eliminate infection, repair damaged tissue and defend against foreign molecules. The innate immune system maintains barriers that prevent microbes from entering and provides the first line of defense against infection. The adaptive immune system is more highly evolved and has the ability to develop defense strategies tailored to different invaders.

Many different types of cells are involved in the immune response. Lymphocytes known as B cells and T cells recognize and eliminate invaders and can also form memory cells that enable a faster response if the same invader is encountered a second time. Cytokines are proteins that help regulate lymphocyte activity and signaling between cells. Antigens are the proteins on the surface of invader cells that the immune system uses as identification tags, producing antibodies that lock on to the antigens and flag those cells for destruction.

Immunotherapy approaches can enhance or suppress the immune response. They can also make it more focused. Some immunotherapies use T cells that are grown in the lab and taught to recognize and attack a specific type of cancer cell or antigen. These cells can be infused into patients, giving their immune response a push in the right direction. Others are based on interleukins, proteins that have the ability to increase growth and activity in the immune system. Vaccines developed to boost the immune response have been used successfully to treat cancer and other diseases.

In some cases, treatments are needed to dampen or turn off an immune response. These types of therapies are used for autoimmune disease, where the immune system becomes the aggressor and attacks healthy cells. Rheumatoid arthritis is one example. These treatments must be carefully tailored to suppress only the part of the immune response that is damaging healthy cells, without turning off the entire system.
Scientists, doctors and entrepreneurs are excited about immunotherapy because it has tremendous potential to help people struggling with many different diseases.

Seattle-based Players in Immunotherapy

Juno Therapeutics
Founded as a partnership among Fred Hutchinson Cancer Research Center, Seattle Childrens and Memorial-Sloan Kettering Cancer Center, New York.

Fred Hutchinson Cancer Research Center
Fred Hutch is an anchor of the Seattle research community and a center for innovation and groundbreaking science.

Adaptive Biotechnologies
A Fred Hutch spinoff that makes diagnostic and monitoring tools based on high-powered immune system sequencing technology.

Immune Design
Launched by researchers from Caltech, the Infectious Disease Research Institute and Fred Hutch, it has since partnered with the New York-based Ludwig Institute for Cancer Research and the Cancer Research Institute to focus on products to help the immune system fight disease.

VentiRX
Led by Robert Hershberg, the former chief medical officer at Dendreon. Hershberg is partnering with Celgene to open an immuno-oncology center in Seattle. Celgene has an option to acquire VentiRx, but so far the company remains independent.

Seattle Genetics
Seattle Genetics is the company startups talk about becoming. Founded in 1998, its focus is on antibody-based cancer therapies.

Benaroya Research Institute
BRI is the headquarters of the Immune Tolerance Network, a collection of 250 research sites around the world pursuing therapies based on immune research.

University of Washington
The UW has one of the top immunology programs in the country and it facilitates partnerships between researchers and industry.

ARCH Venture Partners
Cofounder Robert Nelsen sits on the board of Juno Therapeutics. One of ARCHs managing directors is Steve Gillis, who helped start Immunex. It recently raised $400 million to put toward new approaches that promise big results.