In the latest and largest study yet of a novel technique for treating leukemia patients, researchers have affirmed that it dramatically reduces a common debilitating side effect — chronic graft-vs.-host disease — in those receiving blood stem cell transplants.
The experimental approach, which uses a kind of magnetic filter to remove certain immune cells before transplant, reduced the rate of patients developing chronic GHVD to 7%, compared to rates ranging from 30% to 60% using the current standard of care. It was developed by a Fred Hutchinson Cancer Research Center team led by physician-scientist Dr. Marie Bleakley.
In three separate clinical trials since 2009, the technique produced similar encouraging results even as the pools of patients tested grew larger and were expanded to cover more challenging age groups ranging from 1-60 years old.
“The results were very consistent, and the results were very good,” said Bleakley, who is the lead author of a paper reporting the results of the three combined studies online today in the Journal of Clinical Oncology.
GVHD is often the disturbing price patients pay after bone marrow or blood stem cell transplants that can cure a majority of blood cancers such as leukemia. It is caused when transplanted immune cells from the donor (the graft) perceive as foreign the healthy tissues of the recipient (the host) and attack them.
Its chronic form can damage many organs, including the mouth, lungs and digestive tract, and may require treatments for years with steroids and often other immunosuppressive medication.
“It is a very serious medical condition that can cause ill health and disability,” said Bleakley, who holds the Gerdin Family Endowed Chair for Leukemia Research at Fred Hutch. “Many patients with moderate to severe chronic GVHD can’t work, for example, and kids with it often can’t go to school, or grow and develop more slowly because of the severity of complications.”
Her Hutch team and collaborators from other institutions — including senior author Dr. Warren Shlomchik of the University of Pittsburgh School of Medicine — reported on results in 138 patients who enrolled in trials between 2009 and 2020.
The technique used in these experiments has remained the same since the team developed it more than a decade ago. It employs a process that uses magnets to remove “naïve T cells” from the mixture of blood cells from a donor that are to be transplanted into the patient.
Along with the potent brew of blood stem cells that form the basis of a new, cancer-free immune system, transplant patients receive a considerable dose of tag-along blood components, including infection-fighting T cells.
Many of them are “memory” T cells that come to the patient pre-programmed to fight the same infections they and their ancestors encountered during the life of the donor. That’s a good thing, as they can protect recovering patients from common germs as their new immune systems take root. But trailing along is a large contingent of naïve T cells — about a third of all T cells collected — which like green recruits have not been put to work.
Unfortunately, these naïve cells are primed to go after the first “foreign” cells they encounter, which may be the patient’s own tissues. Preclinical research performed by Shlomchik, Bleakley and others established naïve T cells as a major driver of GVHD, and Bleakley’s team developed their "magnetic bead" technique to take those cells out of the transplant equation.
'We’re trying to thread the needle between leaving everything in — and getting a lot of graft-vs.-host disease — and taking everything out and getting infections. Selective depletion of naïve T cells is trying to get to that fine balance.'
Standard transplant protocols call for suppressing T cells with drugs, but drugs carry their own side effects. Another experimental approach is to remove all T cells before the transplant, but studies show this leaves patients more vulnerable to infections, and their survival odds are not as good. Bleakley calls her approach a “graft-engineering strategy” to deplete naïve T cells selectively.
“We’re trying to thread the needle,” she said, “between leaving everything in — and getting a lot of graft-vs.-host disease — and taking everything out and getting infections. Selective depletion of naïve T cells is trying to get to that fine balance.”
Her approach borrows from a 30-year-old technique used by basic researchers to separate cells in biological laboratories: They tap magnetism to pull them out of the mix.
The key to the naïve T cell depletion process is to use laboratory-made immune proteins called antibodies that latch onto proteins — dubbed CD45RA — found on the surface of all naïve T cells and a few memory T cells. And carried like a backpack on each of these antibodies is an extraordinarily tiny iron bead.
Naïve T cells are therefore coated with iron-bearing antibodies, latched to the telltale CD45RA proteins, and voila: They are drawn by a magnet out of the soup of about-to-be transplanted immune cells.
Bleakley estimates that for every 100 million naïve T cells collected for transplant, the depletion technique takes out all but about 2,500. That is a 40,000-fold reduction.
Over the course of 12 years, the combined trials suggest that, while systematic naïve T cell depletion is not the only possible solution to reducing chronic GVHD, it may be the most effective one.
Bleakley said that, in addition to the very low, 7% incidence of chronic GVHD (most of which was mild) among study participants, three other measures described in the study are of keen interest to patients. After three years, 77% of participants were alive, most of them (68% of total participants) without any relapse or chronic GVHD. Among those whose leukemia did not relapse, 92% were alive.
“Based on the results of what, after all, is a single-arm trial, our technique looks like it may be better than all the competing approaches,” she said.
Her caveat about the single arm trial design — where all patients receive the new treatment approach — is why she couches her conclusions with “probably.” A more definitive answer awaits results of trials in which results from the selective naïve-T cell depletion technique are compared to those of participants randomly assigned to a competing technology. Two such trials are now enrolling patients. Bleakley is principal investigator for both of them.
One mid-sized Phase 2 trial — at Fred Hutch, the University of Pittsburgh Cancer Institute and Moffitt Cancer Center in Tampa, Florida — compares the magnet-depletion technique with an alternative, drug-based T-cell depleting regimen. The results that trial could determine if a definitive, large-scale Phase 3 study should follow.
A second trial, enrolling at several children’s hospitals across the country, will assign participants aged 6 months to 22 years to transplants using either bone marrow or stem cells from circulating blood — the latter depleted of naïve T cells using Bleakley’s technique.
Until these exacting, time-consuming trials are completed, leukemia patients facing transplantation at hospitals throughout the world have little choice — outside of clinical trials — but to receive standard-of-care therapies. Such treatments still hold promise of a lifesaving cure but carry an inherent risk of chronic GVHD.
The results of the combined trials of the transplant technique are welcome news for Dr. Curtis Mack, a Tucson radiation oncologist. In 2013, he became involved in the trials, not as a physician, but as a leukemia patient.
Familiar with Fred Hutch’s reputation as a premier center for bone marrow transplantation, he enrolled as one of 35 participants in the first of the three just published clinical trials testing the naïve T cell depletion technique.
Mack and his partner, Darrell Leetham, moved to Seattle for 6 months for his transplant and recovery period. He experienced no chronic GVHD symptoms. Back in Tucson, he was soon running again with his beloved Weimaraners. Exactly one year after diagnosis he returned full-time to his work treating cancer patients, and as for himself now, he said, “I feel that I am cured.”
“I am happy, physically and mentally,” Mack said. “The only thing I might blame the Hutch for is being a little slower in my running.”
At 57, he still runs half-marathons, but claims he does not run competitively, because “I no longer expect to win” — quickly adding that he “is still faster than many of my friends who are 20 years younger.”
Mack said his time as a leukemia patient has made him a better cancer doctor. He readily shares his story with patients facing their own life-threatening diseases. “I think I relate easier to patients after experiencing much of what they are experiencing themselves,” he said.
The trials reported in the new paper were funded by the National Institutes of Health, the Damon Runyon Foundation, the Richard Lumsden Foundation, the Leukemia and Lymphoma Society, and the Burroughs Wellcome Fund.
Sabin Russell is a former staff writer at Fred Hutchinson Cancer Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and he wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT and a freelance writer for the New York Times and Health Affairs.
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