For individuals battling some of the most aggressive forms of blood cancer, a stem cell transplant remains the most potent weapon with the potential for a cure. However, the specter of cancer recurrence following transplantation often leaves clinicians with a narrow range of subsequent 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 by genetically modifying donor stem cells before transplantation. This innovative strategy aims to enhance the safety and efficacy of follow-up cancer treatments by selectively removing a specific protein from donor cells. This targeted removal allows therapies designed to attack that protein to effectively combat cancer while simultaneously sparing the vital, healthy transplanted cells.
The findings from this significant study, conducted at the Siteman Cancer Center – a joint venture of Barnes-Jewish Hospital and WashU Medicine – and 14 other leading medical centers across the United States and Canada, were recently published in the esteemed scientific journal Nature Medicine. This research represents a critical advancement in the fight against recalcitrant blood cancers, offering a glimmer of hope where options were previously scarce.
A Paradigm Shift in CAR-T Therapy for Difficult-to-Treat Blood Cancers
The core of this breakthrough lies in its potential to overcome a significant hurdle that has historically limited the widespread success of Chimeric Antigen Receptor T-cell (CAR-T) therapy, particularly in certain aggressive blood cancers. According to Dr. John F. DiPersio, MD, PhD, the Virginia E. & Sam J. Golman Professor of Medicine at WashU Medicine and the corresponding author of the study, the gene-editing approach has the capacity to unlock new therapeutic avenues for diseases like acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
CAR-T therapy, a revolutionary form of immunotherapy, has demonstrated remarkable efficacy against several forms of blood cancer. However, its application in AML and MDS has been hampered by a critical biological challenge: the presence of shared protein targets on both cancerous cells and healthy myeloid cells, including the very donor stem cells crucial for transplantation. When CAR-T cells are engineered to target such a shared protein, they risk indiscriminately attacking healthy blood stem cells alongside malignant ones.
This collateral damage can trigger a severe and potentially life-threatening inflammatory response, a condition known as cytokine release syndrome. Furthermore, it can dilute the therapeutic impact of the CAR-T cells themselves, as a significant portion of these engineered immune cells end up targeting healthy tissues instead of concentrating their attack on the cancerous invaders. This diversion of therapeutic resources ultimately compromises the treatment’s effectiveness against the malignancy.
The foundational concept behind this innovative strategy to circumvent this problem was initially conceptualized by Dr. Miriam Y. Kim, MD, who is now an assistant professor of medicine at WashU Medicine. Dr. Kim’s pioneering research began during her postdoctoral fellowship at the University of Pennsylvania and continued within Dr. DiPersio’s laboratory at WashU Medicine. She later established herself as an independent investigator in the WashU Medicine Division of Oncology, where she also actively treats patients and contributes to research at Siteman Cancer Center. Her early work laid the critical groundwork for the subsequent clinical trial.
The Strategic Removal of CD33: A Dual Benefit Approach
The clinical trial meticulously enrolled patients diagnosed with AML and MDS who received donor stem cells that had been genetically engineered to eliminate the expression of a specific protein, known as CD33. The overarching objective was to cultivate a population of healthy blood cells that would be impervious to therapies specifically designed to target CD33, thereby creating a protective shield.
"We are immensely encouraged by the results of this study, which demonstrate that a CD33-deleted stem cell transplant yields outcomes that are strikingly similar to those observed with 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 be able to combine this innovative approach with CD33-targeted immunotherapies, such as CAR-T cells, thereby significantly expanding and improving treatment paradigms for patients afflicted with these particularly aggressive blood cancers."
Further underscoring the promise of this technology, Dr. DiPersio and his research collaborators have also reported on a compelling single-case study involving a patient with high-risk AML. This patient underwent a transplant with CD33-deleted stem cells. When the cancer unfortunately recurred, 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. Remarkably, this patient, who had one of the most aggressive subtypes 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 expression. This critical finding provided definitive evidence that the genetically engineered donor cells had successfully engrafted and established themselves within the patient’s bone marrow. Dr. DiPersio served as the senior author on this groundbreaking case study, which was published in October 2025 in the journal JCO Precision Oncology.
Shielding Healthy Blood Cells: The Precision of CD33 Targeting
CD33 emerges as a particularly attractive target for this therapeutic strategy due to its unique expression pattern. The protein is predominantly found on blood-forming cells and is notably absent from most 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 problems, indicating its dispensability for overall health.
The underlying principle of this approach posits that following a successful transplant with CD33-deleted stem cells, any remaining cells expressing CD33 are likely to be cancer cells. Consequently, a CAR-T therapy or another form of immunotherapy specifically designed to target CD33 could then selectively eliminate these malignant cells while leaving the healthy, donor-derived blood cells unharmed. This precision targeting minimizes the risk of damaging the newly established blood system.
The phase 1/2 multicenter trial involved the enrollment of 30 adult patients diagnosed with AML or MDS who were deemed to be at a high risk of disease relapse. Prior to transplantation, the donor stem cells underwent modification using CRISPR gene-editing technology to effectively remove the CD33 protein. The resulting product, a population of CD33-deleted stem cells, has been designated by the investigational name tremtelectogene empogeditemcel (trem-cel). This innovative cellular therapy was developed by Vor Biopharma, a biotechnology company that also provided funding for the clinical trial.
Testing the Resilience of Gene-Edited Cells Against CD33-Targeted Therapy
To rigorously evaluate the capacity of the gene-edited stem cells to withstand therapies directed at CD33, participants in the trial also received a post-transplant maintenance treatment. This maintenance therapy involved the administration of gemtuzumab ozogamicin, a drug that, while not a CAR-T therapy, is an engineered antibody designed to recognize CD33. Upon binding to CD33-expressing cells, the antibody delivers a potent anti-cancer drug directly to these cells.
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 being investigated in clinical trials for CD33-positive MDS. While this treatment has shown promise in preventing relapse, its clinical utility has been historically limited by significant side effects, including liver toxicity and the destruction of healthy blood cells. Patients treated with conventional gemtuzumab ozogamicin can experience dangerously low counts of white blood cells, red blood cells, and platelets, increasing their susceptibility to infections and bleeding.
Successful Engraftment of Gene-Edited Cells: A Foundation for Recovery
A critical outcome observed in the trial was the successful engraftment of the transplanted stem cells in all 30 patients by day 28 post-transplantation. Engraftment signifies that the donor stem cells have successfully migrated to the bone marrow and have commenced the process of producing new blood cells. Some patients achieved this vital milestone even earlier. Furthermore, platelet production, a key indicator of a healthy blood system, returned on average by day 16. These recovery timelines were found to be comparable to those typically observed with standard stem cell transplantation, suggesting that the genetic modification did not impede the fundamental engraftment process.
The average survival rate in the trial was just over 14 months. Nineteen patients received at least one cycle of gemtuzumab ozogamicin as part of a carefully designed dose-escalation protocol. This protocol allowed researchers to meticulously identify a safe and effective recommended dose for the maintenance therapy. Importantly, across the various dose levels, patients were able to maintain their blood cell counts. This finding strongly suggests that the gene-edited transplant effectively shielded them from the severe drops in blood cell counts that are a common and debilitating consequence when this maintenance therapy is administered following a conventional stem cell transplant.
Side Effect Profile Remains Consistent with Standard Transplants, but with a Crucial Difference
The side effects experienced by patients during the trial were, in general, 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 condition where the donor’s immune cells attack the recipient’s healthy tissues.
During the study period, seven patients unfortunately succumbed to their disease or treatment-related complications. Four of these deaths were attributed to the progression of the underlying cancer, while three were linked to transplant-related complications, including kidney failure, liver toxicity, and sepsis. While these outcomes highlight the inherent risks associated with treating such aggressive diseases, the critical distinction lies in the observed protection of healthy blood cells from the maintenance therapy.
Dr. DiPersio emphasized that the findings from this trial provide a robust foundation for the development of future treatment strategies. These strategies will likely involve the synergistic combination of CD33-deleted stem cell transplantation with CD33-targeted immunotherapies. The ultimate goal is to empower clinicians to mount a more aggressive assault on cancer cells while simultaneously preserving the integrity of the healthy donor cells that are essential for reconstituting the patient’s blood system. This dual-action approach holds the promise of significantly improving survival rates and the quality of life for patients with otherwise intractable blood cancers.
This pioneering research was made possible through financial support from Vor Biopharma. It is noteworthy that several co-authors of the published work were employees of Vor Biopharma at the time the research was conducted, underscoring the collaborative nature of this scientific endeavor between academic institutions and the biotechnology industry. The successful outcome of this trial marks a significant step forward, potentially redefining the treatment landscape for aggressive blood cancers and offering renewed hope to patients and their families.
