By Hendra Lukman 
A groundbreaking antibody therapy developed at Stanford Medicine has demonstrated its potential to prepare patients for stem cell transplants without the need for the harsh and toxic regimens of chemotherapy or radiation, according to promising results from a Phase 1 clinical trial. This innovative approach, which has successfully conditioned three young patients with Fanconi anemia, marks a significant advancement in making life-saving transplants more accessible and less debilitating, particularly for individuals with rare genetic disorders. The research, published in the esteemed journal Nature Medicine, suggests a paradigm shift in transplant preparation, offering hope for a future where the risks associated with these complex medical procedures are substantially mitigated.
The initial focus of this pioneering study was on individuals suffering from Fanconi anemia, a rare and severe inherited disorder characterized by progressive bone marrow failure and a predisposition to certain cancers. The condition impairs the body’s ability to repair DNA damage, leading to a critical deficiency in the production of essential blood cells—red blood cells, white blood cells, and platelets. Without timely intervention, patients with Fanconi anemia face a grim prognosis, often succumbing to bleeding or life-threatening infections due to their compromised immune systems. Traditional stem cell transplantation has been the most effective treatment, offering a chance for cure by replacing the diseased bone marrow with healthy donor stem cells. However, the preparative regimens required to eliminate the patient’s own faulty stem cells—typically high-dose chemotherapy, such as busulfan, and/or radiation—carry significant toxicity, including severe side effects, secondary cancers, and treatment-related mortality, making the procedure exceptionally dangerous for these already vulnerable patients.
"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," stated Agnieszka Czechowicz, MD, PhD, assistant professor of pediatrics and co-senior author of the study. "Specifically, we could eliminate the use of radiation and genotoxic chemotherapy called busulfan, with exceptional outcomes." This breakthrough directly addresses the long-standing challenge of balancing the necessity of transplant conditioning with the unacceptable risks posed by conventional methods.
The Phase 1 trial enrolled three children diagnosed with Fanconi anemia, all under the age of 10, each with distinct genetic variants of the disease. The novel protocol involved administering a single intravenous dose of an antibody targeting CD117, a protein predominantly found on the surface of blood-forming stem cells, approximately 12 days prior to the transplant. This antibody, identified as briquilimab, was designed to selectively deplete the patient’s own hematopoietic stem cells, thereby clearing the way for the donor’s cells to engraft. Crucially, this targeted approach circumvented the need for systemic radiation or the highly toxic busulfan chemotherapy. Following the antibody infusion, patients received standard immune-suppressing medications, but no genotoxic agents.
A New Era in Transplant Conditioning
For decades, the standard procedure to prepare a patient for a stem cell transplant has involved ablative conditioning regimens. These treatments aim to eradicate the patient’s existing bone marrow and immune system, creating space for the donor stem cells and preventing the recipient’s body from rejecting the transplant. Historically, this has been achieved through intense chemotherapy, often including agents like busulfan, a potent alkylating agent known for its genotoxicity and broad range of side effects, and/or total body irradiation. While effective in clearing the bone marrow, these methods are associated with significant short-term morbidities, including mucositis, nausea, vomiting, hair loss, and profound immunosuppression, as well as long-term risks such as infertility, cataracts, and a substantially increased risk of developing secondary malignancies later in life. In fact, estimates suggest that nearly all Fanconi anemia patients treated with conventional methods develop secondary cancers by age 40.
The Stanford Medicine team’s innovative strategy leverages the power of targeted antibody therapy. Briquilimab, the antibody used in the trial, binds to the CD117 receptor, a key marker on hematopoietic stem cells. This binding effectively flags these cells for removal by the patient’s immune system, or through other mechanisms of antibody-mediated clearance, without causing the widespread cellular damage associated with chemotherapy and radiation. This "depletion" process is designed to be precise, minimizing collateral damage to other healthy tissues and organs.
"This is a testament to years of foundational research," explained Dr. Czechowicz, tracing the lineage of the discovery back to her undergraduate work with Irving Weissman, MD, a pioneer in stem cell biology and former director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. Their early studies in mice demonstrated the feasibility of eliminating stem cells using CD117-blocking antibodies, laying the groundwork for the development of a human-compatible therapeutic. The subsequent identification of briquilimab and its successful translation into clinical trials represent a significant leap forward, building upon decades of dedicated research aimed at enhancing the safety and efficacy of stem cell transplantation.
Overcoming the Donor Match Hurdle
Beyond revolutionizing the conditioning regimen, the Stanford team also addressed another formidable obstacle in stem cell transplantation: the persistent challenge of finding suitable donors. Historically, the requirement for a near-perfect human leukocyte antigen (HLA) match between donor and recipient meant that a significant percentage of patients, estimated at up to 40%, were unable to proceed with a transplant due to the unavailability of a compatible donor. This scarcity disproportionately affects minority populations and individuals with rare HLA types.
To broaden the donor pool and increase transplant accessibility, the researchers implemented a modified approach to donor bone marrow preparation. This involved enriching the donated marrow for CD34-positive cells—the very stem cells responsible for blood production—while simultaneously depleting immune cells known as alpha/beta T-cells. The removal of these T-cells is critical, as their presence in the transplanted graft is a primary driver of graft-versus-host disease (GVHD), a potentially life-threatening complication where the donor’s immune cells attack the recipient’s tissues. This innovative "haplo-identical" transplant strategy, pioneered by researchers like Alice Bertaina, MD, PhD, allows for the use of stem cells from half-matched donors, most notably parents, who are readily available for most children needing a transplant.
"We are expanding the donors for stem cell transplantation in a major way, so every patient who needs a transplant can get one," emphasized Rajni Agarwal, MD, professor of pediatric stem cell transplantation and co-first author of the study. This dual approach—a non-toxic conditioning regimen combined with an expanded donor pool—significantly enhances the likelihood of a successful transplant for a wider range of patients.
Ryder’s Remarkable Recovery: A Glimpse of the Future
The profound impact of this new therapy is vividly illustrated by the story of Ryder Baker, an 11-year-old from Seguin, Texas. Ryder was the first child to receive the experimental treatment at Lucile Packard Children’s Hospital Stanford in early 2022. Prior to the transplant, his life was significantly hampered by Fanconi anemia. His mother, Andrea Reiley, described him as perpetually fatigued, lacking the stamina to fully engage in childhood activities.
"He was so tired, he didn’t have stamina. It’s completely different now," Ms. Reiley shared, recounting the dramatic transformation in her son’s health and vitality. "Fanconi anemia doesn’t slow him down like it used to." Today, Ryder is a picture of robust health, brimming with energy. He recently completed fifth grade, actively participates in sports, and has even been recognized with an "Up and Coming Player" award from his school soccer team. His recovery exemplifies the potential of this less toxic approach to restore not just health, but also the quality of life for children affected by severe genetic disorders.
Even with the improved safety profile, stem cell transplantation remains a demanding medical intervention. Ryder experienced a hospital stay of over a month and temporary side effects such as exhaustion, nausea, and hair loss. Ms. Reiley spoke with poignant honesty about the emotional toll of witnessing her child endure these challenges, stating, "It was heartbreaking to see him go through things like that—I’d rather go through it than my child. I felt the heartbreak for him, and now he doesn’t have to."
Since his recovery, Ryder has experienced significant physical growth, gained weight, and no longer suffers from the frequent illnesses that once plagued him. "It used to be huge hits when he would get sick at all, and I really don’t have to worry about that anymore," Ms. Reiley said, her voice filled with relief. She also instills in Ryder a sense of purpose, telling him that his experience as one of the pioneering patients offers hope to others. "I think he takes a lot of pride in that, too," she added.
Broader Implications and Future Directions
The success of this Phase 1 trial offers a beacon of hope for a wider patient population. While stem cell transplants are most commonly associated with the treatment of blood cancers, where the bone marrow is infiltrated with malignant cells, the researchers envision expanding their application to a broader spectrum of inherited diseases. As these transplants become safer and more tolerable, their potential to treat conditions beyond hematological malignancies will undoubtedly increase.
The research team is actively pursuing this vision. A Phase 2 clinical trial is now underway, enrolling more children with Fanconi anemia to further validate the efficacy and safety of the antibody-based conditioning. Furthermore, the team plans to investigate the applicability of this novel approach to other rare bone marrow failure syndromes, such as Diamond-Blackfan anemia, which shares some pathophysiological similarities with Fanconi anemia.
Even for patients with blood cancers, where the eradication of malignant cells remains paramount, the antibody-based conditioning could offer significant benefits. Researchers are exploring its potential use in elderly cancer patients who may not be able to withstand the rigour of traditional high-dose chemotherapy or radiation. "That population is often at a disadvantage," Dr. Agarwal noted. "It may provide us with a way to treat them with less intensity so it’s possible for them to get a transplant." The development of next-generation antibody-based treatments is also on the horizon, aiming to further refine outcomes and address remaining challenges.
The original trial data revealed remarkable engraftment rates. Within two weeks of the transplant, the donated stem cells had successfully taken root in the patients’ bone marrow. None of the three children experienced graft rejection. By one month post-transplant, donor cells had already replaced nearly their entire own bone marrow cell population. The researchers had initially set a target of achieving just 1% donor cell presence, a conservative goal for early-stage trials. However, two years later, all three children achieved nearly 100% donor cell chimerism, indicating complete and robust engraftment.
"We’ve been surprised by how well it’s worked," Dr. Czechowicz admitted. "We were optimistic that we would get here, but you never know when you’re trying a new regimen." This level of success far exceeded expectations and underscores the potent efficacy of the antibody in facilitating successful engraftment.
A Collaborative Endeavor
This groundbreaking research is the product of extensive collaboration and support. In addition to Drs. Czechowicz, Agarwal, and Bertaina, co-senior author Matthew Porteus, MD, PhD, and a multidisciplinary team of researchers from institutions including 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. were instrumental in the study’s design and execution.
The research received crucial funding from anonymous donors, the California Institute of Regenerative Medicine, and the Fanconi Cancer Foundation. Jasper Therapeutics provided the investigational antibody, briquilimab, and the Stanford Clinical Trial Program offered essential support for the study’s implementation. This collective effort highlights the power of interdisciplinary collaboration in advancing medical science and improving patient care.
For families facing the daunting prospect of a stem cell transplant, the availability of less toxic options offers immense relief and renewed hope. "When I counsel families, their eyes start to shine as they think, ‘OK, we can avoid the radiation and chemo toxicity’," Dr. Agarwal shared, reflecting the profound emotional impact of this therapeutic advance. The journey from experimental research to clinical application has been long and arduous, but the results from this Phase 1 trial signal a transformative new chapter in the treatment of Fanconi anemia and potentially many other life-threatening diseases requiring stem cell transplantation.