The cancer killers

Hutch Magazine

The cancer killers
Kristin Kleinhofer

Kristin Kleinhofer

Photo by Robert Hood / Fred Hutch News Service

EVERYTHING HAD FAILED KRISTIN KLEINHOFER. First, her body — invaded by leukemia in 2010. And then, her treatments — a chemotherapy slog that spanned parts of four years, causing infections, fevers, nausea, rashes, abscesses, jaundice and leaky heart valves, yet delivering just two temporary remissions. 

By autumn 2014, the leukemia was back. Kleinhofer saw one shot at survival: immunotherapy. She learned that scientists at Fred Hutchinson Cancer Research Center were genetically modifying patients' immune systems — specifically their T cells — to seek and destroy precisely her type of advanced disease. She landed a spot in the Seattle trial. She received one IV bag of her own re-engineered immune cells.

It worked. The leukemia became undetectable in her blood. That allowed her, three months later, to undergo a successful double cord blood transplant at Seattle Cancer Care Alliance, Fred Hutch's treatment arm. She's remained in remission since.

Her path to remission relied on two pivotal collaborations: Chats among three physicians at three medical centers ushered her into the Hutch trial, and a cross-continent partnership that began years earlier laid some of the critical, scientific groundwork that kept Kleinhofer alive.

That alliance between Fred Hutch immunotherapy researcher Dr. Stan Riddell and German microbiologist and immunologist Dr. Dirk Busch began with a fellowship meant to encourage scientists from across the planet to join forces. After securing that funding, they linked their labs and minds eight years ago to better understand the unique behaviors of single T cells, and then use those cells in immunotherapies to attack cancers and infections in patients.

"Vice President [Joe] Biden was recently at the Hutch and this is one of his big ideas [for the Cancer Moonshot]: How do we get scientists to share more openly?" Riddell said. "I think [in teaming with Busch] we moved the field forward in ways that are still playing out."

They also proved that collaboration could thrive amid the usual fight for research dollars — a reality Riddell also mentioned to Biden.

"Funding these kinds of initiatives is unique and actually something that's missing in science," Riddell said. "[Our partnership] is an example of the kind of success we can have in taking this approach."

In addition to Biden's push to shatter silos, the vice president listed crucial areas of focus, including immunotherapy, precision medicine, public-private partnerships and data sharing.

At Fred Hutch, thought leaders in those areas opt to brainstorm with counterparts at other institutions to speed cancer cures.

While researchers often work solo, they realize their potential can be exponential when they band with peers. But that requires scientists to set aside any sense of competition to link with the best person, regardless of where they work.

In the realm of cancer research — where many organizations may chase the same dollars — these covenants are built on openness, trust and the humbling knowledge that lives are on the line, researchers say. Rivalries, they know, tend to slow the process and the cures.

For patients like Kleinhofer, such collaborations can ultimately erase late-stage disease and sometimes change the course of science.

"That's why I feel very blessed — all these amazing doctors getting me back into remission," Kleinhofer said. "They all want to fight for your life."

Dr. Stan Riddell and Dr. Dirk Busch: Uniting for cures

Dr. Stan Riddell and Dr. Dirk Busch

Near midnight, they walked through the English Garden, a vast Munich park packed with streams, foot bridges, tree groves, beer gardens, even some sheep. Riddell and Busch were headed back from a casual dinner at Busch's house, bound for Riddell's hotel.

Busch had a pitch. A decade earlier, he'd learned of Riddell's pioneering T-cell studies. Busch found the blossoming science so intriguing, he moved his own research in that direction. Now, he wanted to team with Riddell to study T-cell immunology, ultimately taking their discoveries to patients. The pact would require Riddell to work at Busch's lab and live in Munich for months at a time. Riddell's wife and family would join him on those trips.

"I wanted to take you through this way because I wanted you to see how beautiful Munich is," Busch told him that night in 2008.

The stroll helped close the deal.

“Intellectually, we were open in terms of sharing, in terms of discussion. But I think [our collaboration] also reflects a deep commitment both of us had to succeeding. … It’s remarkable the impact that our work has had.”

— Dr. Stan Riddell

"It didn't take much convincing," Riddell later recalled. "He really reached out to me not just as a scientific collaborator but as a person. That was the kind of relationship we would really have to have to make this project successful."

Some eight years later, the Fred Hutch immunotherapy pioneer and the German immunologist operate Focus Group Clinical Cell Processing and Purification, part of the Technical University of Munich. Their group works to develop clinical cell therapeutics to treat infections and certain cancers. The Institute for Advanced Study funded Riddell's involvement and the pair's subsequent immunotherapy research via a fellowship worth more than $100,000.

Indeed, immunotherapy's core principle is to customize the body's natural defenses to fight disease. While that emerging science is showing immense promise, progress doesn't happen in a vacuum.

Riddell and Busch had been individually fascinated by the curing potential of T cells — white blood cells that can detect abnormal cells, including cancerous cells. Subsets of T cells can be removed from patients, reprogrammed genetically and returned to the body to kill cancer, researchers have found.

"But in order to do that, the critical element was to have technologies that would allow you to purify those cells and to really study how they could work and how they could be used," Riddell said. "Dirk, as part of his translational work, was really [focused on] how to develop technologies to be able to do that."

“Out of this really developed a wonderful friendship and, I think, a lot of contributions to the field. … We never want to actually quit.”

— Dr. Dirk Busch

"Stan's work and our work in Munich," Busch agreed, "came together very tightly to really develop these kinds of tools. So, now, we have something we can move forward to the patient."

Their collaborative success has energized the two scientists to hunt for what they call "new beginnings" and fresh partnerships, including talking with researchers who are exploring tissue engineering and tissue regeneration.

"We don't view the relationship as something that is done. … I don't think this has an end," Riddell said. "I don't think I've ever been more excited about the work that we're doing and the potential of the science. That really comes from the collaboration I've had with Dirk."

"It's a really nice example," Busch said, "of what science can be about."

Dr. Eric Holland and Dr. Franziska Michor: No room for egos

Eric Holland and Franziska Michor

Their natural banter showed — and flowed — when Dr. Eric Holland and Dr. Franziska Michor fielded a simple question: What projects have you worked on together?

"This whole space that we’re in was unoccupied by anybody, let alone either of us. We filled it up with stuff that wasn’t going to be where either one of us was going."

— Dr. Eric Holland

"Franziska and I have been collaborating for … five years?" said Holland, a brain cancer researcher and neurosurgeon at Fred Hutch.

"No, much longer than that," replied Michor, a professor of computational biology at Dana-Farber Cancer Institute in Boston.

"Thirty-five years?"

"More like that," she said, in on the joke. "I think 10 years, no?"

"Ten years, you're right. Anyway, a long time."

Chemistry is crucial — both in crafting cures and in the collaborations that accelerate those advances. Indeed, Holland and Michor have forged a long alliance built equally on personal rapport and academic generosity.

They met as researchers at Memorial Sloan Kettering Cancer Center in New York City, pulled together by a grant meant to show how mathematicians could collaborate with cancer biologists. Holland's team helped write the grant. Michor and others created the science.

Their study was rooted in taking measurable pieces of biology, like the rate of a tumor's growth, then creating mathematical models to represent those infinitesimal changes.

By combining their expertise in cancer biology and computational modeling, they believe their collaboration could result in better treatment for patients — improving existing therapies like radiation for brain cancer.

“It’s never just a collaboration between us, it’s also a collaboration between our students and postdocs.” 

Dr. Franziska Michor

Next, the two researchers want to test a new radiation schedule in a clinical trial. "Together, we've achieved a lot more than the sum of our parts," Holland said.

In 2013, Holland went west, recruited by Fred Hutch to become the director of the Human Biology Division. Michor had moved as well, to Dana-Farber. Their combined science continued to thrive despite their 3,000-mile separation. They have now co-authored 11 papers.

At the heart of their partnership lies an understanding — in the end, it doesn't matter who gets the praise or the points for shared discoveries.

"You have to have a broad enough view of the world to know there's a lot of people who know a good deal more about stuff than you do, and you respect them for it," Holland said. "The motivation has to be to achieve the goal, whatever it takes, as opposed to just get the credit for what you have done.

"At the end of the day, everybody gets credit and everybody wins."

Dr. Niki Robinson and Elaine Cheung: Forging a public-private partnership

Dr. Niki Robinson and Elaine Cheung

Dr. Niki Robinson had an urge to celebrate. But in that happy moment, her partner in the months-old venture was 800 miles south in the Bay Area.

So Robinson grabbed her cellphone. Instead of calling, the vice president of Business Development and Industry Relations at Fred Hutch punched up a short message and hit send.

“I live with a sense of urgency. I definitely get the feeling Elaine does, too.”

— Dr. Niki Robinson

Elaine Cheung checked her phone at the offices of GRAIL Inc., a company formed to enable cancer screening from a blood test. Cheung saw a new text from Niki. No words, just emojis: three champagne bottles blowing their corks. Elaine promptly fired back her own emojis: one thumbs-up and five martini glasses.

They had just sealed an agreement for their two organizations to work together.

"We want to get things done," recalled Cheung, head of Business Development at GRAIL. "We go fast and hard. We want to make our institutions and our organizations successful. We want to advance the science."

"We have a cadence that would probably make lots of people dizzy," Robinson added, making Cheung laugh. "Everything has a sense of urgency. The faster that we move this relationship … think about what that potentially could mean to a patient."

In real time, the pact was consummated with remarkable swiftness. In March 2016, they met for the first time in Robinson's Seattle office. The deal between Fred Hutch and GRAIL was signed about two weeks later.

That speed was fueled by a shared vision. Their multifaceted research and technology partnership meshes with the larger quests of both Fred Hutch, where "cures start here," and of GRAIL, which uses an eight-word mission statement: "Detect cancer early, when it can be cured."

“We do feel like the scale of what we’re trying to do could impact tens of thousands, if not millions, of people someday. We want to try to accelerate that as quickly  as possible.”

— Elaine Cheung

GRAIL is developing a nucleic acid-based blood test that will be used to diagnose tumors in patients before they show symptoms — at early stages when the odds of curing malignancies are far higher, the company says.

Marrying early detection — a core of Hutch science — with a company driving to get just such a product to market underscores the value of public-private partnerships, and how they help make it possible to cure cancer, Robinson said.

"There's no way you can do this in one organization. The only way to do this in my mind — and it should be on everyone's mind — is to collaborate," Robinson said. "They're doing exactly what we are so excited about. We just hope to have more partners that are very GRAIL-like and very Elaine-like."

Matthew Trunnell and Dr. Gad Getz: Science by the numbers

Matthew Trunnell and Dr. Gad Getz

They share a history — enormous computer banks built to analyze cancer genomes. They expect to share a future — leveraging Big Data and the cloud to speed cancer cures.

They also share nicknames.

Matthew Trunnell is the chief information officer at Fred Hutch — and he's "Matter" to longtime colleague Dr. Gad Getz.

Getz is director of the Cancer Genome Computational Analysis group at the Broad Institute of MIT and Harvard — and he's "Gaddy" to Trunnell.

“What has to happen is a shift toward what’s being called a team science approach. … It’s a different way of doing science.”

— Matthew Trunnell

For years, they worked together at Broad.

"I was the one (at Broad) telling Gaddy that he had to buy more discs and more computers because I was running the research computing infrastructure," Trunnell said.

"Matter was responsible for all the IT," Getz said. "We grew in this period of time of needing more resources and understanding how to use them better and then in leading the vision of going to the cloud."

At Broad, that project is colorfully known as FireCloud — a cloud-computing platform used for analyzing genomic data, including data from The Cancer Genome Atlas. (TCGA is a federally funded program to catalog genetic mutations responsible for cancer.)

FireCloud is already open to the Broad Institute. Soon, that same infrastructure will be open to the pubic — a potential collaboration bonanza for participating scientists. In short, cancer researchers will log in from their computers and create workspaces with their own collaborators. That includes scientists at Fred Hutch, Getz said.

"We, together with the Hutch, could create projects that we will collaborate based on this — so analysts at Broad and the Hutch would see the data, run jobs, see the results [and] interact on these data," Getz said. That potential collaboration is still in the planning stage, Trunnell said. But the Hutch has its own collection of biospecimens, and the idea is to eventually incorporate into FireCloud the data generated by various research projects involving those specimens. At the same time, Hutch scientists will have access to the massive wealth of genomic data on FireCloud, Trunnell said.

"The Hutch can move much more quickly by leveraging work that's already been done elsewhere," Trunnell said. "I absolutely could build out a computational infrastructure. I've done it before. I did it at Broad. [But] I have no interest in doing that because it doesn't move science forward fast enough.

“I would want to see a future where every patient is in some sort of a clinical trial.  … That only would come by collaborating between multiple centers … then collecting the data and analyzing in a systematic way.” 

— Dr. Gad Getz

"To make science go fast, being able to partner extramurally is really key."

"We call it 'democratizing the access to data,'" Getz added. "So now that platform can be used by many collaborators focusing their time on the actual science … not [on] 'Where's my file?' or 'Why is my job not running?' or 'I need to buy more hard drives,' which used to be the case."

The big goal behind Big Data is to develop new, more targeted treatments for patients based on their own genes, and the genes of their cancers. By understanding which gene mutations exist in which patients, doctors could better predict which patients are most likely to respond to specific therapies and which are more apt to develop a resistance, Getz said.

To scale that scientific mountain, scientists and engineers must next look at hundreds of thousands of genomes, Trunnell said. But in time, when a patient enters the clinic, their genome will tell doctors what course of treatment would work best — and offer a likely prognosis, researchers predict.

In short: The promise of precision medicine rests with more teamwork.

"Gaddy is the scientist-architect. What I bring is the engineering," Trunnell said.

"We both understand the problems, we understand the needs," Getz said. "And we understand that by collaborating together, we will get much bigger results."

Rachel Tompa, Sabrina Richards and Susan Keown also contributed to this story. Write to Bill Briggs at bbriggs@fredhutch.org.

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