By Hendra Lukman 
For patients battling some of the most aggressive forms of blood cancer, a stem cell transplant has long represented the most potent weapon in the medical arsenal, holding the singular promise of a cure. However, the persistent specter of cancer recurrence post-transplantation has historically left clinicians with a dwindling array of follow-up treatment options. Now, a groundbreaking clinical trial spearheaded by researchers at the Washington University School of Medicine in St. Louis is illuminating a path forward, suggesting that genetically modifying donor stem cells prior to transplantation could usher in an era of safer and potentially more effective post-transplant cancer therapies. This innovative strategy involves the precise removal of a specific protein from donor cells, thereby enabling targeted therapies to precisely attack cancerous cells while preserving the integrity of crucial healthy transplanted cells.
The pivotal study, conducted across the renowned Siteman Cancer Center – a collaborative effort between Barnes-Jewish Hospital and WashU Medicine – and extending to 14 additional leading medical centers throughout the United States and Canada, has yielded results published in the esteemed journal Nature Medicine. This research marks a significant leap in the ongoing battle against hematological malignancies, particularly those that have proven recalcitrant to existing treatments.
Overcoming a Critical Hurdle in CAR-T Therapy
The potential of this gene-editing approach to overcome a significant impediment that has constrained the efficacy of CAR-T cell therapy in certain blood cancers was highlighted by the study’s corresponding author, John F. DiPersio, MD, PhD. Dr. DiPersio, who holds the Virginia E. & Sam J. Golman Professorship of Medicine at WashU Medicine, emphasized the transformative implications of this advancement.
CAR-T (Chimeric Antigen Receptor T-cell) therapy, a cutting-edge form of immunotherapy, has demonstrated remarkable success against a subset of aggressive blood cancers. However, its application has been less impactful for diseases such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The central challenge, as explained by Dr. DiPersio, lies in the unfortunate overlap of target proteins. Many proteins found on the surface of AML and MDS cancer cells are also present on healthy myeloid cells, including the vital donor stem cells that are the cornerstone of a successful transplant. Consequently, if CAR-T cells are engineered to target one of these shared proteins, they risk indiscriminate destruction, attacking both malignant cells and essential healthy blood stem cells.
Such collateral damage can precipitate a dangerous inflammatory cascade, a potentially life-threatening complication for transplant recipients. Moreover, it can dilute the effectiveness of the cancer treatment itself, as a substantial proportion of the meticulously engineered CAR-T cells are diverted to attack benign targets, rather than concentrating their formidable power on eradicating the cancerous invaders.
The conceptual foundation for circumventing this critical issue was initially articulated by Miriam Y. Kim, MD, now an assistant professor of medicine at WashU Medicine. Dr. Kim embarked on this research during her tenure as a postdoctoral researcher at the University of Pennsylvania, continuing her investigations within Dr. DiPersio’s laboratory before establishing herself as an independent investigator within the WashU Medicine Division of Oncology. She concurrently treats patients at Siteman Cancer Center and actively contributes to its research endeavors.
The Precision Removal of CD33 from Healthy Stem Cells
The clinical trial specifically investigated the impact of genetically modifying donor stem cells to eliminate a protein known as CD33. The 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 exhibits outcomes very similar to those of 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 hopeful that we will be able to integrate this approach with CD33-targeted immunotherapies, such as CAR-T cells, thereby enhancing treatment options for patients grappling with these particularly aggressive blood cancers."
In a compelling illustration of the therapy’s potential, Dr. DiPersio and his colleagues have also documented a single case involving a patient diagnosed with high-risk AML. This individual underwent a stem cell transplant utilizing CD33-deleted stem cells. When the cancer regrettably reappeared, the patient was subsequently treated with CD33-targeted CAR-T cells, derived from the T cells of the same donor who had provided the initial stem cells. Remarkably, 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. Furthermore, normal blood cell production was successfully restored, and all of the patient’s blood cells were found to be devoid of CD33. This crucial finding served as definitive evidence that the genetically engineered donor cells had successfully integrated and proliferated within 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 protein CD33 emerges as an exceptionally attractive target for this innovative strategy due to its specific expression. It is found exclusively on blood-forming cells and is absent from other tissues within the body. Compelling evidence further suggests that CD33 is not indispensable for the normal functioning of blood stem cells. Individuals born without this protein do not appear to experience any related health complications, underscoring its dispensability for robust hematopoietic function.
The underlying rationale is that following a successful transplant with CD33-deleted stem cells, any residual cells in the body that still express CD33 are likely to be cancerous. Subsequently, a CAR-T therapy or another form of immunotherapy designed to target CD33 could then be deployed to precisely eliminate these malignant cells, while leaving the newly established, healthy donor-derived blood cells unharmed.
The phase 1/2 multicenter trial, which enrolled 30 adult patients diagnosed with AML or MDS and deemed to be at high risk of relapse, meticulously evaluated this approach. Prior to transplantation, the donor stem cells underwent modification using CRISPR gene editing technology to achieve the precise removal of CD33. The resulting product, the genetically engineered CD33-deleted stem cell therapy, has been designated tremtelectogene empogeditemcel (trem-cel). This therapy was developed by Vor Biopharma, a company that also provided funding for the study.
Testing a Targeted Cancer Treatment
To rigorously assess the resilience of the edited stem cells against therapies directed at CD33, participants in the trial were also administered a post-transplant maintenance treatment. This treatment involved the administration of gemtuzumab ozogamicin, a drug that, while not a CAR-T therapy, functions as an engineered antibody. This antibody is designed to recognize CD33 and deliver a potent anti-cancer payload directly to cells that express the protein.
Gemtuzumab ozogamicin has received approval from the Food and Drug Administration (FDA) for the treatment of CD33-positive AML and is currently under investigation in clinical trials for CD33-positive MDS. While this therapy has demonstrated utility in mitigating the risk of relapse, its broader application has been hampered by significant side effects, including liver toxicity and damage to healthy blood cells. Patients treated with gemtuzumab ozogamicin can experience dangerously low counts of white blood cells, red blood cells, and platelets, jeopardizing their overall health and recovery.
Gene-Edited Cells Demonstrate Successful Engraftment
A critical measure of success in stem cell transplantation is engraftment, the process by which transplanted stem cells successfully migrate to the bone marrow and begin producing new blood cells. In this trial, all 30 participating patients achieved engraftment by day 28 post-transplantation, signifying that the donor stem cells had effectively taken root and commenced their vital function. Notably, some patients achieved this milestone even sooner. The recovery of platelet production, another key indicator of hematopoietic recovery, occurred by day 16 on average. These recovery timelines were found to be comparable to those typically observed with conventional, unmodified stem cell transplantation, suggesting that the genetic modification did not impede the fundamental engraftment process.
The average survival observed in the trial was just over 14 months. A significant subset of 19 patients received at least one cycle of gemtuzumab ozogamicin as part of a carefully designed dose-escalation protocol. This protocol was instrumental in enabling researchers to identify a recommended dose for future therapeutic applications. Across the various dosage levels administered, patients were able to maintain their blood cell counts. This finding is particularly noteworthy, as it strongly suggests that the gene-edited transplant effectively shielded them from the severe and often debilitating drops in blood cell counts that are frequently encountered when gemtuzumab ozogamicin is administered following a standard stem cell transplant.
Side Effects Remain Consistent with Standard Transplants
The spectrum of side effects encountered during the trial was broadly similar to those commonly associated with standard stem cell transplantation. These included anemia, diminished platelet counts, fever, infections, and graft-versus-host disease (GVHD), a serious complication where the donor’s immune cells mistakenly attack the recipient’s healthy tissues.
During the study period, seven patients succumbed to their disease or complications. 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. These outcomes underscore the inherent risks associated with aggressive cancer treatments and the complexities of stem cell transplantation.
Dr. DiPersio expressed optimism regarding the findings, stating that they provide a robust foundation for the development of future therapeutic strategies. These advanced treatments aim to synergistically combine CD33-deleted stem cell transplantation with CD33-targeted immunotherapies. The ultimate goal is to empower clinicians to more aggressively target and eradicate cancer cells without inadvertently compromising the integrity of the healthy donor cells that are essential for reconstituting the patient’s blood system and facilitating long-term recovery.
This groundbreaking research was made possible through the generous support of Vor Biopharma. It is important to note that several co-authors of the published study were employees of Vor Biopharma at the time the research was conducted, highlighting the collaborative nature of modern medical innovation. The implications of this trial are far-reaching, offering a beacon of hope for patients facing the daunting prospect of aggressive blood cancers and the limitations of current treatment paradigms.
