By Hendra Lukman 
For patients battling some of the most aggressive forms of blood cancer, a stem cell transplant represents a critical, and often the last, chance for a cure. However, the specter of cancer recurrence looms large, frequently leaving oncologists with a limited arsenal of subsequent treatment options. Now, groundbreaking research emerging from the Washington University School of Medicine in St. Louis is illuminating a promising new path forward. A recent clinical trial suggests that by genetically modifying donor stem cells before transplantation, physicians may be able to enhance the safety and efficacy of follow-up cancer therapies, significantly improving outcomes for these vulnerable patients.
This innovative strategy centers on the targeted removal of specific proteins from donor stem cells. By precisely excising these proteins, the modified cells can evade destruction by therapies designed to target them. This allows powerful treatments to focus their attack on malignant cancer cells while leaving the vital, healthy transplanted cells unharmed. 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, offers a beacon of hope in the fight against challenging hematologic malignancies. The pivotal findings were recently published in the prestigious scientific journal Nature Medicine.
Overcoming a Critical Hurdle in CAR-T Therapy
The development of CAR-T (chimeric antigen receptor T-cell) therapy has revolutionized the treatment of certain blood cancers, demonstrating remarkable success. However, its effectiveness has been notably constrained when confronting diseases such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). 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, explained that the gene-editing approach is poised to address a significant impediment that has historically limited the widespread application of CAR-T therapy in these specific blood cancers.
The crux of the challenge lies in the biological overlap between cancerous cells and healthy cells in AML and MDS. Many proteins expressed on the surface of AML and MDS cancer cells are also present on healthy myeloid cells, including the crucial donor stem cells that form the foundation of a successful transplant. When CAR-T cells are engineered to target one of these shared proteins, they risk indiscriminately attacking and destroying not only the cancerous cells but also the essential healthy donor stem cells.
This collateral damage can trigger a severe and potentially life-threatening inflammatory response within the patient’s body. Furthermore, it can dilute the potency of the cancer treatment itself. A significant proportion of the engineered CAR-T cells may end up targeting benign cells, diverting their destructive power away from the malignant cells that require elimination. This reduces the overall concentration of therapeutic agents available to combat the cancer.
The foundational concept for circumventing this critical issue 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 tenure as a postdoctoral researcher at the University of Pennsylvania. She continued this work in Dr. DiPersio’s laboratory at WashU Medicine before establishing herself as an independent investigator within the institution’s Division of Oncology. Dr. Kim also provides clinical care to patients at Siteman Cancer Center and contributes significantly as a research member.
Strategic Removal of CD33 from Donor Stem Cells
The clinical trial detailed in this report involved patients diagnosed with AML and MDS who received donor stem cells that had undergone sophisticated genetic modification. This modification specifically targeted and removed a protein known as CD33. The overarching objective of this precise genetic alteration was to cultivate healthy blood cells that would no longer be susceptible to therapies designed to target CD33.
"We are encouraged by the results of this study showing that a CD33-deleted stem cell transplant looks very similar to the outcomes of standard stem cell transplantation," stated Dr. DiPersio, who also holds the directorship of WashU Medicine’s Center for Gene and Cellular Immunotherapy. "In the future, we are hopeful we will be able to combine this with CD33-targeted immunotherapies, such as CAR-T cells, and improve treatment options for patients with these very aggressive blood cancers."
Adding further weight to these promising findings, Dr. DiPersio and his research collaborators have also documented a compelling single-case study. This report involved a patient afflicted with a particularly aggressive form of high-risk AML. This individual underwent a stem cell transplant utilizing CD33-deleted donor stem cells. Tragically, the cancer eventually recurred. In response, the patient was treated with CD33-targeted CAR-T cells, which were meticulously engineered from T cells sourced from the same donor who provided the initial stem cells.
Remarkably, this patient, who had one of the most challenging and recalcitrant forms of AML, achieved a complete remission. More than a year following the CAR-T therapy, the patient remained cancer-free. Crucially, normal blood cell production also returned, and all of the patient’s circulating blood cells were confirmed to be devoid of CD33. This profound observation provided definitive evidence that the genetically engineered donor cells had successfully integrated and established themselves within the patient’s bone marrow, fulfilling their intended regenerative function. Dr. DiPersio is the senior author of this significant case study, which was published in October 2025 in the journal JCO Precision Oncology.
Shielding Healthy Blood Cells: The CD33 Advantage
The selection of CD33 as the target protein for this innovative strategy is not arbitrary. CD33 presents an attractive candidate for this therapeutic approach due to its specific expression pattern. The protein is predominantly found on blood-forming cells, including hematopoietic stem cells, and is notably absent from most other vital tissues within the body. This restricted expression profile minimizes the risk of off-target effects on healthy organs. Furthermore, existing 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 discernible associated health problems, further underscoring its dispensability in healthy hematopoiesis.
The underlying therapeutic rationale is elegantly straightforward: following a successful transplant with CD33-deleted stem cells, any remaining cells that still express CD33 are likely to be predominantly cancer cells. Consequently, a CAR-T therapy or another form of immunotherapy specifically designed to target CD33 can then be administered. This targeted intervention would effectively eliminate the CD33-positive cancer cells while leaving the newly established, CD33-negative healthy donor-derived blood cells completely unscathed.
The phase 1/2 multicenter trial that yielded these remarkable results enrolled a cohort of 30 adult patients diagnosed with AML or MDS. These individuals were classified as having a high risk of cancer relapse, underscoring the urgent need for more effective treatment strategies. Prior to transplantation, the donor stem cells were meticulously modified using CRISPR gene-editing technology to ensure the complete removal of the CD33 protein.
The resulting genetically engineered stem cell product, characterized by its CD33-deleted status, has been designated by the investigational name tremtelectogene empogeditemcel, or "trem-cel" for brevity. This innovative therapeutic agent was developed by Vor Biopharma, a biotechnology company that provided the funding for this critical clinical study.
Evaluating a CD33-Targeted Cancer Treatment in Practice
To rigorously assess the capacity of the gene-edited stem cells to withstand subsequent therapies directed at CD33, participants in the trial also received a maintenance treatment post-transplantation. This maintenance phase was designed to mimic the scenario where a patient might later require CD33-targeted therapy for residual disease or relapse.
The drug employed in this maintenance phase was gemtuzumab ozogamicin. It is important to note that this is not a CAR-T therapy. Instead, gemtuzumab ozogamicin is an engineered antibody that is specifically designed to recognize and bind to the CD33 protein. Upon binding, it delivers a potent anti-cancer drug directly to cells that express CD33.
Gemtuzumab ozogamicin has received approval from the U.S. Food and Drug Administration (FDA) for the treatment of CD33-positive AML. It is also currently undergoing investigation in clinical trials for CD33-positive MDS. While this antibody-drug conjugate can be effective in helping to prevent cancer relapse, its clinical utility has historically been hampered by significant side effects. These can include severe liver toxicity and damage to healthy blood cells, often leading to dangerously low levels of white blood cells, red blood cells, and platelets, a condition known as pancytopenia.
Successful Engraftment of Gene-Edited Cells Confirmed
A pivotal and highly encouraging finding from 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 reached the bone marrow and have commenced the vital process of producing new blood cells. In fact, some patients achieved this critical milestone even earlier. Furthermore, the recovery of platelet production was observed by day 16, on average.
These timelines for engraftment and platelet recovery were remarkably comparable to the expected outcomes observed with conventional, unmodified stem cell transplantation. This suggests that the genetic modification process itself did not adversely impact the inherent engraftment potential of the donor stem cells.
The average survival observed in the trial cohort 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 the research team to identify a safe and effective recommended dose for the maintenance therapy.
Across the various dose levels of gemtuzumab ozogamicin administered, patients were able to maintain their blood cell counts. This critical finding strongly suggests that the gene-edited stem cell transplant effectively shielded them from the severe and often debilitating drops in blood cell counts that are frequently encountered when this maintenance therapy is administered following a conventional stem cell transplant. This protective effect is a direct consequence of the absence of CD33 on the healthy donor-derived cells.
Side Effects Remained Comparable to Standard Transplants
In terms of safety, the side effects observed during the treatment period were broadly similar to those typically associated with standard stem cell transplantation. These included expected complications such as anemia (low red blood cell count), thrombocytopenia (low platelet count), fever, infections, and graft-versus-host disease (GVHD). GVHD is a serious complication where the donor’s immune cells, now residing in the patient’s body, recognize the patient’s healthy tissues as foreign and attack them.
Despite the advancements, seven patients in the study unfortunately succumbed to their illness. Four of these deaths were attributed to the progression of the underlying cancer, indicating the aggressive nature of the diseases being treated. The remaining three deaths were linked to transplant-related complications, including instances of kidney failure, liver toxicity, and sepsis, a life-threatening response to infection.
Dr. DiPersio expressed optimism regarding the implications of these findings, stating that they provide a robust foundation for the development of future therapeutic regimens. These novel treatments are envisioned to combine CD33-deleted stem cell transplantation with CD33-targeted immunotherapies. The ultimate objective of this synergistic approach is to empower physicians to aggressively target and eradicate cancer cells while simultaneously preserving the integrity of the healthy donor cells that are indispensable for rebuilding the patient’s compromised blood system.
This significant research effort was made possible through financial support provided by Vor Biopharma. It is important to acknowledge that several co-authors of the study were employed by Vor Biopharma at the time the research was conducted. This collaboration underscores the vital role of industry-academia partnerships in driving forward innovative medical solutions. The results from this trial represent a crucial step forward, offering a tangible prospect of enhanced survival and improved quality of life for individuals facing the daunting challenge of aggressive blood cancers.
