Antibody Therapy Offers Hope for Stem Cell Transplants Without Chemotherapy/Radiation | Stanford Medicine

A groundbreaking new approach to stem cell transplantation, developed at Stanford Medicine, is offering renewed hope for children and adults with Fanconi anemia and other rare blood disorders. Researchers have successfully replaced the toxic pre-transplant conditioning of chemotherapy and radiation with an antibody therapy, significantly reducing the risks associated with this potentially life-saving procedure. The findings, published in Nature Medicine, represent a major step forward in making stem cell transplants accessible to a wider range of patients.

Fanconi Anemia: A Genetic Challenge

Fanconi anemia (FA) is a rare, inherited genetic disorder that prevents the body from properly repairing DNA damage. This leads to bone marrow failure, increasing the risk of leukemia and other cancers. Without a stem cell transplant, individuals with FA typically have a limited life expectancy, often succumbing to infections or bleeding by age 10. Stanford Children’s Health notes that the condition disrupts the production of vital blood cells – red blood cells, white blood cells, and platelets – leading to fatigue, poor growth, frequent infections, and excessive bruising.

The Problem with Traditional Transplants

Whereas stem cell transplantation remains the only potential cure for FA, the process itself is fraught with danger. Before a transplant can grab place, the patient’s existing bone marrow must be eliminated to create way for the donor cells. Traditionally, this has been achieved using high doses of chemotherapy and/or radiation. These treatments, while effective at clearing the bone marrow, also cause significant damage to other tissues and suppress the immune system, leaving patients vulnerable to life-threatening complications like graft-versus-host disease (GVHD), where the donor cells attack the recipient’s body. These conditioning regimens can increase the long-term risk of secondary cancers.

Briquilimab: A Targeted Approach

The Stanford team, led by Agnieszka Czechowicz, MD, PhD, and Rajni Agarwal, MD, has pioneered a new approach using an antibody called briquilimab. This antibody specifically targets CD117, a protein found on blood-forming stem cells, effectively removing them without the widespread damage caused by chemotherapy or radiation. Stanford Medicine reports that this targeted approach allows for a safer and more tolerable transplant process.

In a phase 1 clinical trial, briquilimab was administered to three children with Fanconi anemia prior to receiving stem cell transplants from their parents. All three patients were under 10 years old and had different genetic variants of FA. The results were remarkable: within two weeks of the transplant, the donor stem cells had successfully taken root in the patients’ bone marrow, and by one month, donor cells had nearly fully replaced their own. Two years later, all three children have maintained nearly 100% donor cell chimerism – meaning their blood is now entirely derived from the donor cells – and are doing well.

Expanding Donor Options

Beyond reducing toxicity, the new protocol also addresses another significant challenge in stem cell transplantation: finding a suitable donor. Historically, up to 40% of patients couldn’t receive transplants due to a lack of a fully matched donor. To overcome this hurdle, the Stanford team modified the donor bone marrow before transplantation, enriching it for CD34+ cells (the donor’s blood-forming stem cells) while removing immune cells called alpha/beta T-cells, which are responsible for GVHD. This technique, pioneered by Alice Bertaina, MD, PhD, allows for safe transplants from half-matched donors, such as parents, significantly expanding the pool of potential donors. ScienceDaily highlights this as a key benefit of the new approach.

Ryder’s Story: A Life Transformed

Eleven-year-old Ryder Baker of Seguin, Texas, was the first patient to receive the antibody-based transplant at Lucile Packard Children’s Hospital Stanford in early 2022. Before the transplant, Ryder suffered from debilitating fatigue and frequent illnesses. Today, he is thriving. His mother, Andrea Reiley, describes a dramatic transformation: “He was so tired, he didn’t have stamina. It’s completely different now.” Ryder has regained his energy, finished fifth grade, plays sports, and even received an “Up and Coming Player” award from his school soccer team.

Looking Ahead: Broader Applications and Ongoing Research

The success of this trial opens the door to potential applications beyond Fanconi anemia. Researchers believe the antibody approach could also benefit patients with other inherited diseases that require stem cell transplants, such as Diamond-Blackfan anemia and certain types of bone marrow failure. They are exploring whether the antibody can be used to improve transplant outcomes for elderly cancer patients who may be unable to tolerate traditional conditioning regimens.

Stanford’s team is currently leading a phase 2 clinical trial involving more children with Fanconi anemia. They are also developing next-generation antibody-based treatments to further refine and improve outcomes. As Agnieszka Czechowicz, MD, PhD, explains, “We’ve been surprised by how well it’s worked. We were optimistic that we would get here, but you never know when you’re trying a new regimen.”

The research team acknowledges that while the initial results are promising, long-term follow-up is crucial to assess the durability of the response and monitor for any potential late effects. The team is also focused on understanding the underlying mechanisms of action of briquilimab to optimize its use and identify potential biomarkers that could predict treatment response.