Photo by Bo Jungmayer / Fred Hutch
"Around day 14 or so after his T cells, his comments to me were that the lymph nodes in his neck felt like ice cubes melting"
- Dr. David Maloney, Fred Hutch
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 a first-in-human trial.
Dr. David Maloney, a 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 the patient’s disease.
“We were kind of on pins and needles,” Maloney said. “The first infusions are always somewhat nerve-wracking.”
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 said, “so they’re not totally full of nerves.”
Days later, something remarkable happened. “Around day 14 or so after his T cells, his comments to me were that the lymph nodes in his neck felt like ice cubes melting,” Maloney said. “We knew that was not the chemotherapy because I’d just given him higher doses of chemotherapy, and he had not even responded at all. So we knew the T cells were clearly doing something — in a very resistant tumor.”
Photo by Robert Hood
For Maloney, it offered a fresh glimpse of the possible: a future in which cancer could be wiped out with something as simple to administer as an infusion of T cells, leaving healthy cells untouched so the patient would experience few side effects.
“Once you see that happen once, you know you’re really on to something — that this is a really exciting new area of therapy,” he said.
But in research, exploring entirely new areas is only possible with the help of donations.
Potential too huge to ignore
In April, Fred Hutch received the largest single donation in its history: a transformative $20 million gift from the Bezos family to help unlock the potential of immunotherapies for lung, colon, breast, pancreatic, ovarian and other common solid-tumor cancers.
"We’ve followed the work Fred Hutch scientists have been conducting over the last few years,” said Mike Bezos when the family announced the gift, “and are so encouraged by the spectacular results in patients with leukemia and lymphoma. The potential to now attack other cancers with this approach is too huge not to take this research to the next level."
BOLD IDEAS NEED BIG SUPPORT
While the concept of using the human immune system against cancer is not new, what is new — and still rapidly evolving — is scientists’ ability to manipulate that system to create therapies targeted so specifically at cancer that they don’t affect healthy cells.
Research teams across the country and around the world are exploring a variety of ways to achieve that goal, and a growing number of stories in the media are raising the public profile of cancer immunotherapy.
Results from trials of the early incarnations of these experimental therapies keep pointing to their huge potential, which the Bezos family’s gift will help Fred Hutch researchers tap.
Dr. Larry Corey, Fred Hutch’s president and director, emphasized that the Bezos family’s gift will enable Hutch researchers to be “as creative as people can be to move the field of immunotherapy forward. We want to improve our potential to effectively treat and cure cancer. That is really what the goal is.”
The donation also provides a foundation that allows each additional dollar raised, whether from an individual or through a granting agency, to be transformative as well. Just as the scientists learn from every experiment and every trial participant — whether results confirm hypotheses or dismantle them — “catalytic philanthropy” at the Hutch is about maximizing the power of every contribution. And it’s a model with a track record.
A challenge made and met
In 2009, the Bezos family, which is active in the Seattle philanthropic community as well as with programs around the country, made its first gift to immunotherapy research at Fred Hutch. The family structured it as a challenge, as Jackie Bezos said at the time, “to help (the Hutch) secure, for the long term, a diverse group of supporters and to rally a community around science that has the potential to benefit us all.”
Rally it did. The $10 million challenge was met in just a year, and in the nearly five years since that gift, more than 3,800 individuals and organizations joined the ranks of benefactors supporting immunotherapy research at Fred Hutch. That backing helped build essential infrastructure that few research centers have in-house as well as fast-track projects, particularly those aimed at improving T-cell therapies.
The science gained momentum, and approaches that appeared increasingly promising in the lab steadily advanced toward the ultimate testing ground: human trials.
From pie in the sky to reality
Fred Hutch currently has half a dozen early-phase clinical trials open to test various forms of T-cell therapy in dozens of patients with leukemias and lymphomas, Merkel cell carcinoma (an uncommon but particularly aggressive skin cancer), melanoma and certain sarcoma subtypes.
In the past decade, more than 150 patients have enrolled in Hutch trials of various cell-based immunotherapies alone, and with the growing number of new trials on the horizon, another 150 could be treated with T-cell therapies in the next 18 to 24 months.
“This is still in its infancy, it’s still early on,” Maloney said of the treatments now being tested, “but it’s moved from something pie in the sky to reality.”
Maloney’s trial involves genetically programming patients’ T cells to produce a chimeric antigen receptor, or CAR, that enables them to target certain leukemia and non-Hodgkin lymphoma cells for elimination. CARs blend the power of antibodies — proteins that specialize in precise recognition of disease targets — with the prowess of T cells, which, once triggered, can eliminate diseased cells and, often, retain the memory of that threat in order to swiftly respond should it reappear in the future. Unlike antibodies, which are only effective until the body breaks them down, T cells may continue to multiply, serving as a living therapy.
Maloney works closely with “a great clinical team” of research nurses, trial coordinators and other highly specialized staff members, as well as Fred Hutch research colleague Dr. Cameron Turtle. Turtle, who leads another ongoing CAR T-cell trial, is instrumental in coordinating the production of CAR T cells and in the sophisticated monitoring of patients’ immune responses following therapy. This work is critical for the team to understand exactly how the treatment works.
Engineering and producing these special T cells is labor-intensive. In addition to refining the therapeutic effects, scientists will need to develop ways to scale the technology before it can become a mainstream approach. But from the patient’s point of view, the procedures can be simple enough to seem almost anticlimactic — if the stakes weren’t so high.
Early-phase trials like this one are, Maloney said, “pretty much reserved for patients who have failed primary options.”
Although participants have typically exhausted the standard treatments for their disease, some of the responses to the experimental therapy have been dramatic, with tumors vanishing from scans within weeks or months of the T-cell infusion.
But not every patient reacts that profoundly, and that, too, drives Maloney and his colleagues.
“There have been some patients where we’ve treated them and had initially good results and then their lymphomas come back or the T cells haven’t persisted,” Maloney said. “We need to figure out why it works in some people and why it doesn’t work in some people. We’re learning a tremendous amount from every single patient … But we’ve seen enough encouraging activity to know that this process can work, can work extraordinarily well and, at least in our trials so far, has been associated with manageable toxicity.”
Behind the Scenes
Developing T-cell therapies requires extensive study and refinement in the lab before patient trials can ever be launched.
1) Specific T cells are isolated from a blood sample and multiplied in an incubator.
2) Multiplied T cells are counted under the microscope using a hemacytometer.
3) T cells are concentrated in a centrifuge before undergoing detailed studies to learn how they can be manipulated to effectively treat cancer.
4) To generate a therapy for use in patients, all the steps of isolating, engineering and preparing the T cells happen in a specialized clean facility.
Bubble rooms give way to breakfast out
Joanne Rochester, a Fred Hutch/Seattle Cancer Care Alliance transplant nurse, has cared for the 14 patients treated to date on Maloney’s trial and is encouraged too. “I am seeing people go through this with less-severe side effects,” she said.
And Rochester has seen a lot since she started working with Fred Hutch trial participants during the early days of bone marrow transplantation. Those blood cancer patients faced an arduous journey, many quarantined in sterile laminar air-flow rooms — known as “bubble rooms” — to protect them from infection after their own immune systems had been destroyed with high-dose chemotherapy and total- body irradiation.
Rochester said she and the other nurses had to gown up in sterile garb to go in and treat patients. “Only one person at a time could go in,” she recalled, as patients waited for the donor cells to take root, or engraft, and blossom into a new, cancer-free immune system.
When Fred Hutch researchers started transplanting stem cells taken from circulating blood rather than from bone marrow in the 1990s, “it seemed like a whole new arena because we were doing almost the whole treatment outpatient,” Rochester said. “It was really a huge step.”
The new immunotherapy trials are direct descendants of those efforts, offshoots of discoveries made about the immune system’s curative role in transplantation. Rochester said the ongoing trials are giving her that same sense of momentous change, sometimes in surprising ways.
One recent Saturday morning, for instance, Rochester ran into one of her patients and the patient’s spouse at a favorite neighborhood restaurant. Less than three weeks after receiving the experimental T-cell therapy, “there they are, having breakfast,” Rochester said. “Seeing them out at a restaurant — wow, they’re having a normal life — that you don’t see with transplant patients.”
The potential of what’s to come
What could come next, however, as new technologies converge with generous philanthropic support to ignite more progress in cancer immunotherapy, has people even more excited.
Fred Hutch Executive Vice President and Deputy Director Dr. Fred Appelbaum, who started working on immune-based therapies at the Hutch in 1978 when he was recruited to help pioneer bone marrow transplantation, said, “On the one hand, you have this extraordinary evidence that the immune system can eradicate common solid tumors. And on the other hand, we have, for the first time, the ability to really probe these tumors and figure out what is abnormal about them. We can sequence the DNA and find out their mutations and therefore the abnormal proteins and therefore the targets for immunotherapy.”
Identifying and understanding new targets is one of a host of challenges presented by solid-tumor cancers. Target discovery is an enormous undertaking given the diversity of tumor types and subtypes, but Fred Hutch researchers have already found a handful of candidates in breast, lung and Merkel cell cancers.
Scientists at Fred Hutch and elsewhere are also learning how cancers deflect and usurp the body’s defenses. Tumors can recruit other cells to their neighborhood that dampen the immune response. They can erect walls of tissue that keep therapies, including chemotherapies, from penetrating. The uptick in genetic changes that happens in cancer cells can also cause them to stop producing the very markers that T cells and other parts of the immune system use to recognize the disease.
Cloaking themselves in anonymity, shielding themselves behind healthy tissue, or throwing up smoke screens of cells and molecules that shut off the immune response — once they get a foothold, cancers rarely cut the immune system any slack. Undaunted, teams at Fred Hutch are actively working to overcome these challenges, including by combining immunotherapies with conventional treatments and with other new immunotherapies.
Those are just some of the first next steps. Other Hutch researchers are looking even farther ahead. One possibility under study involves injecting nanoparticles that would redirect the immune system to attack cancerous tumors. In such a scenario, T cells wouldn’t need to be isolated from the patient and manipulated in special labs; instead they would be programmed right inside the patient’s body, perhaps within days of diagnosis.
Though such a treatment does not yet exist, it is no longer a mere fantasy. But turning ideas like these into cancer treatments requires time and funding. The new gift from the Bezos family will kick start these newest waves of work by bringing “the broader expertise that’s here at the Hutch into immunotherapy,” said Dr. Stanley Riddell, an internationally renowned immunotherapy researcher and member of Fred Hutch’s Clinical Research Division.
Experts in fundamental cancer biology, clinicians with vast experience in treating patients with common solid-tumor cancers, and immunologists can team with leaders in techniques like genomic profiling and mass spectrometry to learn how current immunotherapies work — or don’t — and develop even better strategies going forward. Those kinds of collaborations are “not the kind of thing you can write a grant for,” Riddell said.
Despite the complexity of the task, there is an undeniable sense of optimism that pervades the offices, labs and meeting spaces at Fred Hutch. Each win reinforces the excitement and each setback only renews the commitment and inspires greater ingenuity. And that’s really how medical advances emerge. The fact that so many supporters are partnering with Hutch research teams to catalyze this work just ensures that the next advances, like those that brought us here, will truly belong to everyone.
“It needs to work better even than it’s working now,” Maloney said of immunotherapy, which is why continued funding for future research remains so critical. “The support of many diverse projects within the study of immunotherapy, it’s exciting. It takes a broad brush to come up with these kinds of breakthroughs.”
Write to Andrea Detter at firstname.lastname@example.org.