By Hendra Lukman 
For patients battling some of the most aggressive forms of blood cancer, a stem cell transplant has long represented the pinnacle of curative treatment. However, the specter of cancer recurrence post-transplantation has persistently loomed, leaving clinicians with a narrow arsenal of subsequent therapeutic options. Now, a pioneering clinical trial spearheaded by researchers at the Washington University School of Medicine in St. Louis is illuminating a path toward safer and potentially more effective follow-up treatments. This innovative approach involves genetically modifying donor stem cells before transplantation, a strategy designed to specifically target cancer cells while preserving the integrity of vital transplanted healthy cells.
The study, conducted across the Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine, alongside 14 other leading medical institutions in the United States and Canada, presents a significant advancement in the fight against diseases like acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The findings, published in the esteemed journal Nature Medicine, detail a sophisticated gene-editing technique that addresses a critical limitation of existing powerful therapies, particularly CAR-T cell therapy.
Overcoming a Major Hurdle in CAR-T Cell Therapy
CAR-T cell therapy, a revolutionary form of immunotherapy where a patient’s own T cells are genetically engineered to recognize and attack cancer cells, has demonstrated remarkable success against certain blood cancers. However, its efficacy has been notably constrained when confronting diseases such as AML and MDS. The fundamental challenge, as explained by John F. DiPersio, MD, PhD, the Virginia E. & Sam J. Golman Professor of Medicine at WashU Medicine and the corresponding author of the study, lies in the shared molecular targets.
"Many proteins found on AML and MDS cancer cells also appear on healthy myeloid cells, including the donor stem cells crucial for transplantation," Dr. DiPersio elaborated. "When CAR-T cells are programmed to target one of these shared proteins, they can inadvertently destroy healthy blood stem cells alongside the cancerous ones."
This collateral damage can trigger a severe and potentially life-threatening inflammatory response, a phenomenon known as cytokine release syndrome. Furthermore, it can dilute the therapeutic impact of the CAR-T cells, as a significant portion of these engineered warriors end up attacking benign targets instead of concentrating their formidable power on the malignant cells.
The conceptual foundation for this ingenious workaround was initially laid by Miriam Y. Kim, MD, who is now an assistant professor of medicine at WashU Medicine. Dr. Kim initiated this research during her postdoctoral fellowship at the University of Pennsylvania and continued its development within Dr. DiPersio’s lab at WashU Medicine before establishing her own independent research program in the Division of Oncology. Her clinical work and research are integral to the Siteman Cancer Center.
The Precision Strike: Removing CD33 from Donor Stem Cells
The cornerstone of the clinical trial involved patients diagnosed with AML and MDS who received donor stem cells that had been meticulously genetically modified to eliminate a specific protein known as CD33. The strategic objective was to engineer healthy blood cells that would become invisible to therapies specifically designed to target CD33.
"We are very encouraged by the results of this study, which demonstrate that a CD33-deleted stem cell transplant yields outcomes remarkably similar to standard stem cell transplantation," stated Dr. DiPersio, who also holds the directorship of WashU Medicine’s Center for Gene and Cellular Immunotherapy. "Looking ahead, our hope is to synergize this approach with CD33-targeted immunotherapies, such as CAR-T cells, thereby enhancing treatment options for individuals afflicted with these particularly aggressive blood cancers."
In a compelling demonstration of the strategy’s potential, Dr. DiPersio and his research team have also documented a singular case involving a patient with high-risk AML. This individual underwent a CD33-deleted stem cell transplant. When the cancer regrettably resurfaced, the patient was subsequently treated with CD33-targeted CAR-T cells, which were derived from the T cells of the same donor who had provided the original stem cells. The outcome was extraordinary: the 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 blood cells were found to lack CD33. This critical finding provided definitive evidence that the genetically engineered donor cells had successfully engrafted and integrated into the patient’s bone marrow. Dr. DiPersio was the senior author of this case study, which was published in October 2025 in JCO Precision Oncology.
Shielding Healthy Blood Cells: The CD33 Advantage
The selection of CD33 as the target for this innovative strategy is not arbitrary. CD33 is an attractive candidate because it is predominantly expressed on blood-forming cells, including leukemic cells, and is largely absent from other healthy tissues. Furthermore, emerging evidence suggests that CD33 is not essential for the normal functioning of blood stem cells; individuals born without this protein generally do not experience related health complications.
The underlying hypothesis is that after a successful transplant utilizing CD33-deleted stem cells, any remaining cells expressing CD33 are likely to be cancer cells. Consequently, a CD33-targeted CAR-T therapy or another form of immunotherapy could then precisely target and eliminate these malignant cells while leaving the healthy, genetically modified donor-derived blood cells unharmed.
Clinical Trial Design and Patient Enrollment
The phase 1/2 multicenter trial was designed to evaluate the safety and preliminary efficacy of this novel approach. It enrolled 30 adult patients diagnosed with AML or MDS who were deemed to be at a high risk of disease relapse. Prior to their transplantation, the donor stem cells underwent modification using CRISPR gene editing technology to excise the CD33 protein.
The resulting product, the genetically modified stem cells, has been designated tremtelectogene empogeditemcel (trem-cel). This innovative cellular therapy was developed by Vor Biopharma, a company that also provided funding for the clinical study.
Testing the Resilience of Gene-Edited Cells
To rigorously assess the ability of the edited stem cells to withstand a therapy directed at CD33, patients in the trial also received a maintenance treatment following their transplantation. This treatment involved the administration of gemtuzumab ozogamicin. It is important to note that gemtuzumab ozogamicin is not a CAR-T cell therapy; rather, it is an engineered antibody that binds to CD33 and delivers a potent anti-cancer drug directly to cells expressing the protein.
Gemtuzumab ozogamicin has received approval from the Food and Drug Administration (FDA) for use in CD33-positive AML and is currently being investigated in clinical trials for CD33-positive MDS. While this antibody-drug conjugate can be instrumental in preventing cancer relapse, its clinical utility has historically been hampered by significant side effects. These can include liver toxicity and damage to healthy blood cells, leading to dangerously low levels of white blood cells, red blood cells, and platelets, a condition known as pancytopenia.
Successful Engraftment and Sustained Blood Cell Production
A critical benchmark for any stem cell transplant is successful engraftment, the process by which transplanted stem cells migrate to the bone marrow and begin producing new blood cells. In this trial, all 30 participating patients achieved engraftment by day 28, a crucial indicator of the transplant’s success. Some patients reached this milestone even sooner, and platelet production was restored, on average, by day 16. These recovery times were comparable to those observed in standard stem cell transplantation protocols.
The average survival observed in the trial was just over 14 months. Nineteen patients received at least one cycle of gemtuzumab ozogamicin as part of a dose-escalation protocol. This phased approach allowed researchers to meticulously identify a recommended safe and effective dose for the maintenance therapy. Across the various administered doses, patients were able to maintain their blood cell counts. This finding is particularly significant, as it suggests that the gene-edited transplant effectively shielded them from the severe drops in blood cell counts that are frequently encountered when gemtuzumab ozogamicin is administered following a conventional stem cell transplant.
Safety Profile and Future Implications
The side effects experienced by patients during the trial were generally consistent with those typically seen in standard stem cell transplantation. These included anemia, low platelet counts, fever, infections, and graft-versus-host disease (GVHD), a serious complication where the donor immune cells attack the patient’s healthy tissues.
During the study period, seven patients succumbed to their illness. Four of these deaths were attributed to the progression of their underlying cancer, while the remaining three were linked to transplant-related complications, including kidney failure, liver toxicity, and sepsis.
Dr. DiPersio emphasized that these findings provide a robust foundation for the development of future treatment paradigms. The ultimate goal is to create a synergistic approach that pairs CD33-deleted stem cell transplantation with CD33-targeted immunotherapies. This combination aims to empower clinicians to attack cancer cells with unprecedented aggression while simultaneously safeguarding the vital donor cells that are indispensable for reconstituting the patient’s blood system.
The potential implications of this research are far-reaching. By mitigating the risk of collateral damage to healthy transplanted cells, this gene-editing strategy could pave the way for more aggressive and sustained application of powerful targeted therapies like CAR-T cells in patients with AML and MDS. This could translate into improved remission rates, longer survival, and a significantly enhanced quality of life for individuals facing some of the most challenging hematological malignancies. The successful engraftment and sustained blood cell production observed in the trial underscore the potential of this technology to fundamentally alter the treatment landscape for these devastating diseases.
This research was supported by Vor Biopharma. Several co-authors were employees of the company at the time the work was conducted, underscoring the collaborative nature of this significant advancement. The continued exploration and refinement of this gene-editing technology hold immense promise for transforming the outlook for patients with aggressive blood cancers.
