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.
Chronic GVHD a 'serious medical condition'
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.