While the researchers tested the protocol on patients with Fanconi anemia, a genetic disease that makes standard stem cell transplant extremely risky, they expect it may also work for patients with other genetic diseases that require stem cell transplants.
“We were able to treat these really fragile patients with a new, innovative regimen that allowed us to reduce the toxicity of the stem cell transplant protocol,” said the study’s co-senior author, Agnieszka Czechowicz, MD, PhD, assistant professor of pediatrics. “Specifically, we could eliminate the use of radiation and genotoxic chemotherapy called busulfan, with exceptional outcomes.”
In the clinical trial, publishing online July 22 in Nature Medicine, the antibody used in combination with other drugs enabled transplants for three children with Fanconi anemia. All three have completed two years of follow-up and are doing well.
“If they don’t get a transplant in time, Fanconi anemia patients’ bodies eventually will not make blood, so they die of bleeding or infections,” said co-first author Rajni Agarwal, MD, professor of pediatric stem cell transplantation. “The reason I am so excited about this trial is that it is a novel approach to help these patients, who are very vulnerable.”
Before undergoing a stem cell transplant — in which diseased bone marrow is replaced by that of a healthy donor — a patients’ own stem cells must be eliminated, typically with radiation or chemotherapy. In the trial, patients were instead injected with antibodies against CD117, a protein on the surface of blood-forming stem cells. The antibody, briquilimab, eliminates blood-forming stem cells without toxic side effects.
Other authors of the study included co-first author Alice Bertaina, MD, PhD, the Lorry I. Lokey Professor, and co-senior author Matthew Porteus, MD, PhD, the Sutardja Chuk Professor in Definitive and Curative Medicine.
Decades of research leads to safer transplant
The team drew upon decades of Stanford Medicine scientific advances to develop a safer technique that also makes stem cell transplants more accessible.
Czechowicz has studied blood-forming stem cells since 2004, when she was an undergraduate student in the lab of Irving Weissman, MD, the Virginia and D.K. Ludwig Professor in Clinical Investigation in Cancer Research who was then the director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. Their work focused on CD117, which regulates the cells’ growth and development. They found that an antibody against CD117 blocked the stem cells’ growth and eliminated the cells from mice without the hazards of radiation and chemo. Together with other Stanford scientists, they subsequently identified the clinical antibody equivalent that was used in this new clinical trial.
This clinical trial also addressed a second challenge in stem cell transplant: In the past, about 35% to 40% of patients who need the transplants for any reason did not receive them because they lacked fully matched donors. But researchers found a way to increase the chance that the transplants would work by modifying the donated bone marrow before giving it to the participants. They enriched for CD34+ cells — the donor’s blood-forming stem cells — by specifically removing a subset of problematic immune cells known as alpha/beta T-cells. The innovation, which was developed by Bertaina and her colleagues before she came to Stanford Medicine, reduces the risk of a transplant complication called graft-versus-host disease, in which immune cells in donated bone marrow attack the recipient. It allows patients to receive cells from someone who shares only half of their immune markers, such as a parent.
“We are expanding the donors for stem cell transplantation in a major way, so every patient who needs a transplant can get one,” Agarwal said.
The first person with Fanconi anemia to benefit from the new approaches was Ryder Baker, of Seguin, Texas, who is now 11. Ryder received a stem cell transplant at Lucile Packard Children’s Hospital Stanford in early 2022 as part of the clinical trial. Today, Ryder’s Fanconi anemia “doesn’t slow him down like it used to,” said his mom, Andrea Reiley. Before the transplant, she said, “He was so tired, he didn’t have stamina. It’s completely different now.”
Ryder, who recently finished fifth grade, is using some of his newfound energy to play sports. He loves pickleball and received an award — Up and Coming Player — from his school’s soccer team.
The researchers hope Ryder will be the first of many kids to benefit from their work.
“Bone marrow or stem cell transplants are most commonly used in blood cancers, in which the bone marrow is full of malignant cells and patients have no other options,” Czechowicz said. “But as we’re making these transplants better and safer, we can expand them to more patients including those with many different diseases.”
A disease of DNA repair
Fanconi anemia interferes with DNA repair. One consequence is impaired development of blood cells, including oxygen-carrying red blood cells; white blood cells needed for immune function; and platelets, which help the blood clot. Patients experience fatigue, reduced growth, frequent infections, and more bruising and bleeding than normal. Eventually, their blood cell production is so diminished they have a life-threatening condition known as progressive bone marrow failure, signs of which develop in about 80% of Fanconi anemia patients by age 12.
Children with Fanconi anemia can become stuck in a catch-22: A stem cell transplant can prevent and treat bone marrow failure, but because their DNA-repair machinery works so poorly, patients are extremely vulnerable to side effects — including cancer — from the chemotherapy or radiation used to prepare for these transplants.
“Right now, nearly all of these patients get secondary cancers by the time they’re 40,” Czechowicz said, adding that her team hopes their new approach will reduce those rates. Fanconi anemia patients are also more vulnerable than other people to complications of graft-versus-host disease.
The three trial participants were all younger than 10 when they received their transplants. They were of different racial/ethnic backgrounds and had different gene mutations underlying their Fanconi anemia.
Each patient received a single intravenous infusion of the antibody 12 days before they were scheduled to receive donated stem cells. Closer to the transplant date, they received immune-suppressing medications typically given before stem cell transplant, but no radiation or busulfan chemotherapy that is typically part of the treatment regimen.
Each patient was then given a stem cell transplant consisting of cells that had been donated by a parent, depleted of alpha/beta T-cells and enriched for blood-forming stem cells. Within two weeks, the donated stem cells quickly took up residence in the patients’ bone marrow. No one experienced graft rejection — a transplant complication in which the patient’s immune system rejects the donated cells — and by 30 days after transplant, the healthy cells from the donors had almost completely taken over the patients’ marrow.
The researchers’ initial goal was to help patients reach 1% donor chimerism, meaning 1% of the bone marrow cells would come from the donor. But two years later, all three patients have close to 100% of their cells from their donors — far better than the researchers expected.
“We’ve been surprised by how well it’s worked,” Czechowicz said. “We were optimistic that we would get here, but you never know when you’re trying a new regimen.”
A medical pioneer
Even with the improved protocol, a stem cell transplant is a big challenge for kids like Ryder, requiring them to spend more than a month in the hospital and endure short-term side effects such as severe exhaustion, nausea and hair loss.
“It was heartbreaking to see him go through things like that — I’d rather go through it than my child,” Reiley said, adding that, fortunately, Ryder remembers little of the experience. “I felt the heartbreak for him, and now he doesn’t have to.”
Since his transplant, Ryder has grown taller, gained weight and become much less susceptible to run-of-the-mill germs, his mom said. “It used to be huge hits when he would get sick at all, and I really don’t have to worry about that anymore.”
Reiley has conversations with her son about how his experience as a medical pioneer is helping experts take better care of other kids. “I think he takes a lot of pride in that, too,” she said.
After more than three decades of administering stem cell transplants with the traditional approach, Agarwal said she loves explaining to patients’ families how much better the new options are.
“When I counsel families, their eyes start to shine as they think, ‘OK, we can avoid the radiation and chemo toxicity’,” she said.
The researchers are now conducting a phase 2 trial of the same protocol in additional children with Fanconi anemia. They also plan studies to test whether the new approach will work for other conditions, including Diamond-Blackfan anemia, another genetic disease that causes bone marrow failure.
Most cancer patients may still require some chemotherapy or radiation to rid them of malignant cells, said the researchers, who noted that another team at Stanford Medicine is testing whether the antibody can help elderly cancer patients who can’t tolerate full doses of radiation or chemotherapy because they are fragile or have diseases in addition to cancer.
“That population is often at a disadvantage,” Agarwal said. “It may provide us with a way to treat them with less intensity so it’s possible for them to get a transplant.”
The group is also working on next-generation approaches that may continue to improve the treatment regimen for patients with Fanconi anemia as well as other grievous diseases.
Other researchers who contributed to the study were from the University of California, San Francisco; Kaiser Permanente Bernard J. Tyson School of Medicine; St. Jude Children’s Research Hospital; Memorial Sloan Kettering Cancer Center; and Jasper Therapeutics Inc.
Study funding came from anonymous philanthropic support and the California Institute of Regenerative Medicine. The antibody, briquilimab, was supplied by Jasper Therapeutics Inc. The Fanconi Cancer Foundation and the Stanford Clinical Trial program also provided clinical trial support and assisted with the execution of the study.
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