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A Twist on Stem Cell Transplants Could Help Blood Cancer Patients

Cathy Doyle felt fine. And in April 2016, when she logged in to a web portal to check the results of some routine blood work, the little numbers on the screen agreed—mostly. But her white blood cell count looked low. She called the doctor’s office. “What's going on?” the chatty, spiritual 58-year-old from Pittsburgh remembers saying.

The staff asked if she’d recently been sick. She had. Doyle caught a bad cough on a family cruise, but it had passed. That might be it, they agreed, but it would be best to come in for more blood tests. “Bless the doctor,” Doyle says. “He just kept hoping it wouldn't be leukemia.”

But her white blood cell count kept falling. Her physician referred her to a hematologist, who biopsied her bone marrow. “It came back positive,” she says. It was leukemia, after all. Specifically, it was acute myeloid leukemia, or AML, which begins in the blood-forming stem cells in bone marrow. These cells normally turn into the red blood cells that carry oxygen and the white blood cells that fight infection. The cancerous cells crowd out the healthy ones; infection risk goes up. The bad cells then spill out of the marrow into the bloodstream and across the immune and nervous systems. The five-year survival rate for AML is under 30 percent.

Doyle’s body was waging a silent coup. To beat it, she would need heavy doses of chemotherapy to wipe out the malignant cells. Doctors could then replenish her blood-making and immune systems with a graft, or a transplant of stem cells harvested from a donor, once she could find a match.

Doyle was peculiarly fortunate: She is the sixth of 10 siblings—and two brothers were perfect matches. But an issue remained: Leukemia patients who get transplants are not off the hook. About half of them relapse. And a stem cell graft risks its own immune problems, if the new cells begin to fight their host in the days, months, or even years down the road. The donor’s immune cells can attack the recipient’s body, a condition called graft-versus-host disease, or GVHD. “They think that there's a virus infecting every cell in the body,” says Warren Shlomchik, who directs the Hematopoietic Stem Cell Transplantation Program at the University of Pittsburgh Medical Center. “Chronic graft-versus-host disease can be crippling—and can kill people.”

For all the things that made Doyle grateful—a potential treatment and donors willing to help—her diagnosis remained severe. “It was very, very scary,” she says. She thought about death: “Was I going to be here for my grandchildren?”

But Doyle’s oncologist asked her to consider a new option. Since 2009, Shlomchik had been running a clinical trial of a different way to do stem cell grafts for people with blood cancers like AML, hoping it can lower the risk of chronic GVHD. The treatment involves carefully filtering out a subset of the donor’s immune cells suspected of triggering it.

Doyle became one of 138 participants. Like the others, she received the filtered grafts—in her case, involving stem cells donated by her brother—after chemotherapy. Oncologists monitored each person’s condition for three or four years. And in results published in January in the Journal of Clinical Oncology, the team writes that their experimental treatment greatly diminished the incidence of chronic GVHD. Typical rates are between 30 and 60 percent. In the study, it dropped to roughly 7 percent.

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“It’s exciting that we could do it,” says Shlomchik.

“This is an important first step,” agrees Nelson Chao, chief of the division of Hematological Malignancies and Cell Therapy at Duke University, who was not involved in the work. It’s hard to retain the benefits of standard stem cell grafts without dangerous overactivity in the immune system, Chao says. These results add steam to a move toward refining grafts to combat chronic GVHD, he says: “Graft engineering is the future of all this.”

In 2020, nearly 475,000 people were diagnosed with leukemia, a broad class of cancers affecting blood cells, according to global cancer database Globocan. More than 300,000 people died of the disease that year. AML is just one form of leukemia, but it accounts for more than 11,000 deaths per year in the United States.

Blood and marrow transplants have been around as leukemia treatments for almost 70 years. They’re an invaluable step after chemo and radiation nuke a person’s cell-making machinery. “You can rescue that toxicity by giving back blood stem cells,” says Shlomchik. “So you can now give doses of chemotherapy that the person would die from.”

But even early on, doctors noticed a dangerous immune response. Then in the 1990s, when he was just starting his career in hematology research, Shlomchik remembers coming across a study that made him realize the power of T cells, a type of white blood cell important for immune function. These relapsed cancer patients had achieved remission after receiving transplants of the cells. “I thought, ‘Wow, this is amazing,’” he says. He called his brother, Mark, an immunologist, and the two arranged to investigate the biology of T cells in search of a way around chronic GVHD.

By 2003 the brothers discovered, in experiments with mice, that a subset called memory T cells did not trigger chronic GVHD. Memory T cells are immune cells that have learned, from exposure, to recognize a particular pathogen. They’re a sort of immuno-veteran compared to “naive” T cells, which have not developed any special detection skills. The naive T cells were the actual troublemakers.

In 2007, Marie Bleakley, a pediatric oncologist and blood and marrow transplantation physician now with the Fred Hutchinson Cancer Research Center in Seattle, began leading an effort to translate the Shlomchiks’ work from mice to humans. The combined team learned how to separate the naive T cells from the memory T cells, basically by pouring the donor’s blood through a special filtering system.

They would start with a bag of the donated fluid—technically a mixture harvested from the donor’s bone marrow containing blood and immune cells. They’d hang the bag above two feet of magnetized tubing on a machine called CliniMACS. Inside the bag, they would also place tiny iron beads, each attached to an antibody that is designed to find and stick to naive T cells. As the fluid ran through the tubing and past more magnets on the machine, the naive cells stuck to the iron beads would stay behind. What remained at the bottom would be a cocktail of memory T cells. “It is simple but elegant,” says Bleakley.

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Their clinical trial for cancer patients began in 2009, starting with a cohort of 35 participants in Seattle and at Yale, where Shlomchik worked at the time. In 2015, Shlomchik’s lab moved to the University of Pittsburgh. And in May 2016, Cathy Doyle received her leukemia diagnosis at a doctor’s office just 13 miles down the road.

Early results from Bleakley and Shlomchik’s initial cohort were already positive by the time Doyle completed chemo and was ready for her transplant. One of her brothers donated his cells, and the research team magnetically removed the naive T-cells. Now they had to wait to see what would happen.

They expected that the first weeks would be bumpy. There are actually two kinds of GVHD: acute GVHD, a common reaction immediately after grafts, and the chronic version that the experiment was designed to avert. Acute GVHD is a sign that the graft is stomping out any remaining cancer cells but also that it is fighting with the recipient’s tissue. Having acute GVHD is the most telling risk factor for getting chronic GVHD. But it can also be temporary, lasting a few months.

For Doyle, the aftermath of the transplant was rough, even compared to chemo. For three months, she was exhausted. She couldn’t keep food down and had mouth sores. “I lost like 60 pounds,” she says.

But after that, things gradually improved. She has not developed signs of chronic GVHD. “Knock on wood,” says Doyle. “We’re five years out, and I haven't had any issues.”

And overall, among the 138 patients, while rates of acute GVHD were unaffected, rates of chronic GVHD went down. Several months post-transplant, when doctors would expect about half of people to deal with chronic GVHD, less than 10 percent did. Over three years of observation, they reported no severe cases of chronic GVHD. “I think we're seeing a really clear consistent signal,” says Bleakley.

“It's especially wonderful for me to see the positive results in the young kids and young adults,” she says, noting that their pediatric cohort included patients as young as 1 year old. Kids that young are less likely to get blood cancers, like leukemia and lymphoma, but they may need stem cell transplants to heal from immunodeficiencies and metabolic or marrow disorders. Chronic GVHD can inflict particular damage on kids—leading to disabilities and social handicaps or preventing them from having a normal childhood.

“This is encouraging and merits further study,” says Corey Cutler, medical director of the Stem Cell Transplantation Program at the Dana Farber Cancer Institute. Depleting naive T cells is just one of several “graft manipulation” ideas that researchers are testing at the moment. “If this trial were offered at my center in a randomized format to confirm this, I would feel comfortable allowing my patients to enroll,” Cutler says. “This is a good one.”

Other experimental approaches deplete T cells completely or use drugs to keep them from reacting with the recipient’s body. So far, none of these approaches have beaten the standard treatment—a bone marrow graft with no T cell filtering—in randomized trials.

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Preventing chronic GVHD with drugs might be cheaper and easier, says Chao. But he notes that this team’s approach is less of a sledgehammer than handicapping all T cell activity: By depleting the naive T cells, it seems you get a more precise or “selective” treatment. The graft still combats the cancer but perhaps not the host.

There are a few important caveats. The team’s trial was designed to test for chronic GVHD, so they can’t make conclusions about whether the experimental graft affects leukemia survival. And the subjects still experience what looks like acute GVHD. But to Shlomchik, eliminating the acute version isn’t the goal. “The goal is to have patients a year or two years out who were cured and have a reasonable quality of life,” he says. “The goal is to have a good life—not die of your disease.”

Chao’s not so sure it even is acute GVHD. He suggests the rashes, sores, and digestive symptoms reported in the trial fit more with something called T cell expansion—basically, T cells repopulating exactly as planned. In that case, these early symptoms are unavoidable, and even desirable. Figuring out the distinction, he says, is “really important. Because if it's just T-cell expansion, you want to just let that happen.”

Over the next few years, Bleakley and Shlomchik will learn even more lessons from randomized trials, which are already underway in four medical centers. In these trials, patients will not know whether the grafts they receive will have the naive T cells removed or not. Bleakley expects those trials to run another three years.

In the years that followed her transplant, Doyle had to get 14 bone marrow biopsies to check for relapses. Today, she is GVHD-free, and her cancer is in remission. “I love to be with my grandkids,” she says. “And this research gave me that. It gave me this life that I'm in right now.”


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