“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 towards 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 the 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 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’s simple but elegant,” says Bleakley.