It wasn’t the leukemia that Gregg Gordon feared the most. When he underwent a cord blood transplant at Fred Hutchinson Cancer Research Center in 2011 to cure his cancer, his blood and immune system had to be destroyed first, leaving him vulnerable until his new healthy donor cells took hold and rebuilt his body’s protective mechanisms.
“I always told people, I wasn’t going to die of leukemia, I was going to die of infection,” said Gordon, 49, a New Yorker and father of two.
But neither of those outcomes came to be. Protecting Gordon was a new cord blood stem cell product designed to reduce his risk of such complications and speed his recovery during this critical period.
The product — more fully described as an ex vivo expanded umbilical cord blood stem cell product — uses blood stem and progenitor cells from donated umbilical cord blood. These stem cells have the potential to develop into any blood or immune cell the body needs.
In the lab, the cells are instructed to multiply, or expand, up to 500 times over (or more), through a signaling pathway initially discovered in the lab of Dr. Irwin Bernstein, head of Fred Hutch’s Pediatric Oncology Program and a member of Nohla’s scientific advisory board.
Once infused into patients, the expanded stem cells rapidly differentiate into the mature cells that are needed to prevent the life-threatening infections and bleeding that are especially common after cord blood transplant. In this way, the mature cells help speed a patient’s recovery — meaning the window when they are vulnerable to infection and other complications is much smaller.
“All physicians who have taken care of patients going through transplant have seen someone die unexpectedly. I feel that risk is unacceptable,” said Delaney, who is Nohla’s chief medical officer. She is also a member of Fred Hutch’s Clinical Research Division and the founding director of the Hutch’s Cord Blood Transplant Program.
Nohla Therapeutics, the latest Fred Hutch spinoff, is a stem cell therapy company focused on developing off-the-shelf, on-demand universal-donor therapies that require no tissue-type matching. The first of these is Delaney’s cord blood stem cell product.
With commercialization, the product has the potential to be available to any doctor around the world to treat patients who need it. To date, the only way to receive the expanded cell product was to be enrolled in a clinical trial at a limited number of academic medical centers.
“We are delighted with the relationship we have formed with the scientific inventors and research team at Fred Hutch, and our executive team is fully committed to further developing and commercializing what we see as a transformative and truly ‘off-the-shelf’ cell therapy,” said Nohla CEO Benjamin Bergo in the company’s press release.
The product is designed to benefit a wide range of patients, not just those who receive a cord blood transplant. Delaney said that her vision for the expanded cord blood product is to reduce the risk of infectious complications in every patient at risk of neutropenia, a life-threatening condition that results most commonly after chemotherapy and increases vulnerability to infection.
The company has licensed seven patent families from Fred Hutch that cover Delaney’s technology platform for creating this and other cellular therapies. This platform is based on fundamental research conducted over two decades by Bernstein’s and Delaney’s teams. Nohla and Fred Hutch have also entered into a collaborative partnership to further develop the technology.
“The discovery by Drs. Colleen Delaney and Irv Bernstein for off-the-shelf cord blood cell expansion is game-changing for so many cancer patients,” said Niki Robinson, Fred Hutch’s vice president of Industry Relations and Business Development. “We are so excited about our partnership with Nohla, and look forward to our collaborative work to further develop this innovative science into lifesaving therapy for patients around the world.”
The product’s potential for wide availability stems from the fact that it doesn’t require HLA (tissue-type) matching. That means “being able to give it to anyone at any time, literally,” Delaney said.
Crystal Day, a 30-year-old Seattle architect, is one of over 100 people who have received the expanded cord blood product so far. Day was infused with the cells along with a transplant of cord blood to treat a relapse of her acute myeloid leukemia in August 2014 as part of Delaney’s ongoing phase 2 randomized clinical trial.
For Day, even getting the chance to participate in the trial was a huge relief.
When Day, who is mixed-race, relapsed and needed a transplant, she couldn’t find a match in her family, or in the worldwide database of mostly white adult stem-cell donors, a scenario that is too common among racial or ethnic minorities who need a transplant.
“It was scary [to relapse],” said Day. “And it was even scarier when they said I didn’t have a match.”
But umbilical cord blood transplantation does not require the close matching that is necessary in transplants of adult blood stem cells. When Day learned about this transplantation option, and that she had a good-enough match, she and her family were overjoyed.
“I called my dad right away. He said, ‘Man, I’d pay a million dollars for that cord blood,’” Day recalled.
It was in the run-up to her transplant at University of Washington that Day learned about Delaney’s trial. She was somewhat unsure at first.
“Just the words ‘clinical trial’ made me kind of hesitate,” she said. But Delaney’s overflowing enthusiasm for the expanded cell product and careful explanations of the potential risks and benefits made Day eager to go ahead.
“I went home afterwards really excited and hopeful that I would get picked,” she said. The next day, Day found out she had been randomly assigned to the group that would receive the expanded cell product.
The infusions of cord blood and expanded cell product are given through an IV, much like any blood transfusion. Once transplanted, Day’s new cells engrafted more quickly than average — around two weeks later — and she was out of the hospital in just four.
Although further studies are still ongoing, Delaney’s team has established the expanded cells’ safety. They have also presented preliminary results suggesting that — just as in Day’s case — the expanded cells reduce time to engraftment and time spent in the hospital, in addition to reducing the risk of infections, severe toxicities after transplant, and treatment-related causes of death.
Outside of transplantation, the expanded product is also being tested as a protective therapy for patients undergoing chemotherapy.
Day said she wishes that she had had an option like this when she developed neutropenia during chemotherapy in 2010 to treat her first bout with leukemia. That experience was a low point for her.
“I was in the hospital for six weeks just for the chemo, because my blood cells wouldn’t recover,” Day said. “That was the worst thing, when I was in there for so long.”
Transplants of blood-forming stem cells, such as those found in bone marrow, were pioneered at Fred Hutch as lifesaving therapies for people with leukemia and other blood disorders. Through transplantation, healthy blood cells replace patients’ diseased ones.
The expanded cell product is the result of decades of research at Fred Hutch. In the early 1990s, Bernstein began to study how an evolutionarily ancient cell-signaling pathway called Notch was involved in the development of blood stem cells into white blood cells and other specialized blood cells.
Cells use Notch signaling to communicate with each other. Like a toggle switch, Notch signals instruct immature cells to either make more of themselves or to differentiate into mature cells. The Bernstein Lab and collaborators proved that blood stem cells use Notch to tell each other which of the two paths to take.
Over the next years, members of the Bernstein Lab developed a promising method to manipulate the Notch pathway using a protein called Delta, tested the method with blood stem cells in mouse models, and began to work with cord blood cell expansion.
A fellow in Bernstein’s lab at the time, Delaney told Bernstein that she wanted to translate the lab’s work on cord blood expansion into the clinic.
“It was kind of ridiculous for anybody at that stage of the game to propose,” Bernstein said, laughing. “It’s early, the amount of regulatory stuff, just the amount of work it required would take almost an entire lab to do it.”’
Nevertheless, “she did it single-handedly, basically,” he said.
It was her patients that made Delaney so determined, she said. Throughout her career, Delaney had watched as patients who were seemingly doing well suddenly get seriously ill or even die from toxicities related to their treatments.
“There’s a real palpable risk,” Delaney said. “When you meet with patients, it’s very easy to tell them you’ve very likely to cure their disease. But there’s a chance they will die in that process.”
She intended to change this.
“What we’re trying to do is make the whole process safer and increase survival while doing so,” Delaney said.
With Nohla’s launch, Delaney will continue to oversee her laboratory at Fred Hutch, run the center’s Cord Blood Transplant Program and take care of patients. But because her product’s commercialization causes a conflict of interests, she is handing off leadership of all her clinical trials of the expanded product to Dr. Filippo Milano, associate director of the cord blood program.
And that change is perhaps the one downside Delaney has about reaching this milestone that she’s been working toward for many years: that she will no longer be able to treat participants in the trials her discoveries have made possible.
“That’s the one thing about this [company launch], that I won’t get that anymore,” she said on a recent day in her office, surrounded by photos of patients she’s treated over the years, her voice suddenly quieter.
One of those photos is of Gordon, the pilot-study participant, walking with his two daughters and his wife, their smiles and their interlocked arms broadcasting joy. Gordon, who now considers Delaney a friend, remembers what it meant to him to have her leading his trial. “I can’t emphasize enough what a special person that Colleen is,” he said.
“These families are looking to me for hope and for not a promise of a cure, not even of survival, but a promise that there’s a chance. To be allowed into that circle of trust is not something I take lightly,” Delaney said. “I develop bonds with them that you don’t find other places. I feel very privileged to be part of their lives no matter what the outcome is.”
The photographs in Delaney’s office tell a story about the lives she’s touched over her career as a physician and a researcher. With Nohla’s launch, Delaney is hopeful that this story broadens to encompass far more patients and families than she could ever hope to meet.
“No matter where they are, no matter what their HLA typing is, no matter in cord blood transplant or in other indications … I want this to be something everyone can get,” she said.
Susan Keown is a staff writer at Fred Hutchinson Cancer Research Center. Before joining Fred Hutch in 2014, Susan wrote about health and research topics for a variety of research institutions, including the National Institutes of Health and the Centers for Disease Control and Prevention. Reach her at firstname.lastname@example.org or follow her on Twitter at @sejkeown.