For patients battling the most formidable blood cancers, a stem cell transplant has long represented the ultimate curative option, a beacon of hope when other treatments falter. However, the specter of cancer recurrence post-transplant has persistently dimmed this hope, often leaving physicians with a dwindling arsenal of therapeutic strategies. Now, a groundbreaking clinical trial spearheaded by researchers at the Washington University School of Medicine in St. Louis is illuminating a new path forward, suggesting that genetically engineering donor stem cells prior to transplantation can significantly enhance the safety and efficacy of subsequent cancer treatments. This innovative approach involves the precise removal of a specific protein from donor cells, thereby enabling targeted therapies to eradicate cancer cells while preserving the integrity of vital transplanted healthy cells.
The pivotal study, conducted across the Siteman Cancer Center—a collaborative enterprise of Barnes-Jewish Hospital and WashU Medicine—alongside 14 other leading medical institutions in the United States and Canada, has yielded promising results published in the prestigious journal Nature Medicine. This advancement holds particular significance for the future of CAR-T cell therapy, a potent form of immunotherapy that has encountered limitations in treating certain aggressive blood malignancies.
Addressing a Critical Hurdle in CAR-T Therapy
Dr. John F. DiPersio, a distinguished figure in hematology-oncology and the Virginia E. & Sam J. Golman Professor of Medicine at WashU Medicine, highlighted the profound implications of this gene-editing strategy. He explained that it has the potential to surmount a major obstacle that has previously constrained the widespread application of CAR-T cell therapy against specific blood cancers.
CAR-T therapy, which involves reprogramming a patient’s own immune T cells to target and destroy cancer, has demonstrated remarkable success in treating certain types of aggressive blood cancers. Nevertheless, its effectiveness has been notably less pronounced against diseases such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The core of this challenge, as elucidated by Dr. DiPersio, lies in the shared expression of certain proteins on both cancer cells and healthy myeloid cells, including the crucial donor stem cells used in transplantation. When CAR-T cells are engineered to target these shared proteins, they risk indiscriminately attacking healthy blood stem cells alongside the cancerous ones.
This collateral damage can precipitate a dangerous inflammatory cascade, known as cytokine release syndrome, which can be life-threatening. Furthermore, such indiscriminate targeting can dilute the therapeutic potency of the CAR-T cells, as a significant portion of these engineered immune cells are diverted to attack healthy targets instead of concentrating their efforts on the malignant cells.
The conceptual genesis of this elegant solution can be traced back to Dr. Miriam Y. Kim, now an assistant professor of medicine at WashU Medicine. Dr. Kim initiated this line of research during her postdoctoral tenure at the University of Pennsylvania and continued its development within Dr. DiPersio’s laboratory at WashU Medicine before establishing her own independent research program in the Division of Oncology. She actively treats patients at Siteman Cancer Center and remains an integral research member of the institution.
The Strategic Removal of CD33 from Healthy Stem Cells
The clinical trial implemented a novel strategy: patients diagnosed with AML and MDS received donor stem cells that had been genetically modified to excise a protein known as CD33. The overarching objective was to cultivate a population of healthy blood cells that would be rendered impervious to therapies specifically designed to target CD33.
"We are encouraged by the results of this study, which demonstrate that a CD33-deleted stem cell transplant yields outcomes remarkably similar to those observed with standard stem cell transplantation," stated Dr. DiPersio, who also serves as the director of WashU Medicine’s Center for Gene and Cellular Immunotherapy. "Looking ahead, we are optimistic that we can integrate this approach with CD33-targeted immunotherapies, such as CAR-T cells, thereby expanding and improving treatment options for individuals afflicted with these particularly aggressive blood cancers."
In a compelling demonstration of this therapeutic paradigm, Dr. DiPersio and his colleagues have also documented a singular case involving a patient with high-risk AML. This patient underwent a CD33-deleted stem cell transplant. When the cancer subsequently reappeared, the patient was treated with CD33-targeted CAR-T cells derived from the same donor who provided the original stem cells. This patient, who had one of the most aggressive forms of AML, achieved a complete remission and has remained cancer-free for over a year following the CAR-T treatment. Crucially, normal blood cell production was restored, and all of the patient’s circulating blood cells were found to lack CD33. This significant finding provided definitive evidence that the genetically engineered donor cells had successfully engrafted and established themselves within the patient’s bone marrow. Dr. DiPersio was the senior author of this accompanying study, published in October 2025 in JCO Precision Oncology.
Shielding Healthy Blood Cells for Enhanced Therapeutic Precision
CD33 emerges as an exceptionally attractive target for this innovative strategy due to its specific localization. The protein is predominantly found on blood-forming cells and is largely absent from other tissues in the body. Furthermore, scientific evidence suggests that CD33 is not essential for the normal functioning of blood stem cells. Individuals born without this protein have not exhibited any associated health complications, further underscoring its dispensability for overall well-being.
The underlying principle of this approach posits that following a successful transplant with CD33-deleted stem cells, any remaining cells in the body that express CD33 are likely to be cancerous. Consequently, a CAR-T therapy or another form of immunotherapy engineered to target CD33 could then effectively engage and eliminate these cancer cells, while leaving the healthy donor-derived blood cells unharmed and intact.
The phase 1/2 multicenter trial enrolled a cohort of 30 adult patients diagnosed with AML or MDS who were identified as being at high risk of disease relapse. Prior to transplantation, the donor stem cells underwent precise modification using CRISPR gene-editing technology to remove the CD33 protein. The resultant product, the genetically modified CD33-deleted stem cell preparation, is known by its investigational name, tremtelectogene empogeditemcel (trem-cel). This therapy was developed by Vor Biopharma, which also provided funding for the study.
Testing a Targeted Cancer Treatment Against CD33
To rigorously assess the capacity of the gene-edited stem cells to withstand a therapeutic regimen specifically directed at CD33, participants in the trial also received a maintenance treatment following their transplantation. This maintenance therapy involved the administration of gemtuzumab ozogamicin. It is important to note that this drug is not a CAR-T therapy but rather an engineered antibody that binds to CD33 and delivers a potent anti-cancer payload directly to cells expressing the protein.
Gemtuzumab ozogamicin has already received approval from the U.S. Food and Drug Administration (FDA) for the treatment of CD33-positive AML and is currently undergoing evaluation in clinical trials for CD33-positive MDS. While this antibody-drug conjugate can play a role in preventing relapse, its clinical utility has been historically limited by significant side effects, including liver toxicity and the unintended destruction of healthy blood cells. Patients treated with this agent can experience dangerously low levels of white blood cells, red blood cells, and platelets, compromising their immune defenses and increasing the risk of bleeding and anemia.
Gene-Edited Cells Demonstrate Successful Engraftment
A critical benchmark of successful stem cell transplantation is engraftment, the process by which the transplanted stem cells migrate to the bone marrow and begin producing new blood cells. In this trial, all 30 participating patients achieved successful engraftment by day 28 post-transplantation, a milestone indicating that the donor stem cells had taken root and commenced their vital function. Notably, some patients reached this crucial stage even sooner. The recovery of platelet production, another key indicator of hematopoietic reconstitution, was observed by day 16 on average. These recovery timelines were found to be comparable to those typically observed in patients undergoing standard stem cell transplantation, suggesting that the genetic modification did not compromise the inherent functionality of the stem cells.
The average survival observed in the trial was just over 14 months. A significant portion of the cohort, nineteen patients, received at least one cycle of gemtuzumab ozogamicin as part of a carefully designed dose-escalation protocol. This phased approach allowed researchers to meticulously identify a safe and effective recommended dose for the maintenance therapy. Across the various dose levels administered, patients were able to maintain their blood cell counts. This finding is particularly encouraging, as it suggests that the gene-edited transplant effectively shielded them from the severe and often debilitating drops in blood cell counts that are commonly associated with the use of this maintenance therapy following a conventional stem cell transplant.
Side Effect Profile Remains Consistent with Standard Transplants
An analysis of the adverse events encountered during the trial revealed that the side effects were broadly similar to those typically associated with standard stem cell transplantation. These included common complications such as anemia, low platelet counts, fever, infections, and graft-versus-host disease (GVHD), a serious complication where the donor immune cells attack the recipient’s healthy tissues.
During the course of the study, seven patients succumbed to their illness. Of these, four deaths were attributed to the progression of their underlying cancer, while the remaining three were linked to transplant-related complications. These transplant-related fatalities were associated with conditions such as kidney failure, liver toxicity, and sepsis, a life-threatening systemic inflammatory response to infection.
Dr. DiPersio emphasized that these findings provide a robust foundation for the development of future therapeutic strategies. The ultimate goal is to create an integrated treatment regimen that combines CD33-deleted stem cell transplantation with CD33-targeted immunotherapies. This synergistic approach aims to empower physicians to mount a more aggressive assault against cancer cells without inadvertently sacrificing the essential healthy donor cells required for the patient’s blood system to regenerate.
This pioneering research was generously supported by Vor Biopharma. It is noteworthy that several co-authors of the study were employed by Vor Biopharma at the time the research was conducted, highlighting the collaborative nature of this translational science endeavor. The implications of this research extend beyond the immediate patient cohort, potentially reshaping the landscape of treatment for a broad spectrum of aggressive blood cancers.
