By Hendra Lukman 
For individuals battling some of the most aggressive forms of blood cancer, a stem cell transplant has historically represented the most promising, and often the sole, curative treatment option. However, the specter of cancer recurrence following transplantation has remained a significant clinical challenge, leaving physicians with a narrow therapeutic arsenal. Now, groundbreaking research from Washington University School of Medicine in St. Louis suggests a paradigm shift: genetically modifying donor stem cells before transplantation could usher in an era of safer and potentially more potent follow-up cancer therapies. This innovative strategy involves the precise removal of a specific protein from donor cells, enabling targeted therapies to eradicate cancer while preserving the integrity of the vital transplanted cells.
The pivotal clinical trial, a collaborative effort involving researchers at the renowned Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine, alongside 14 other leading institutions across the United States and Canada, has yielded results published in the prestigious scientific journal Nature Medicine. This advancement holds particular promise for overcoming a critical hurdle that has previously limited the efficacy of CAR-T cell therapy in certain challenging blood cancers.
The CAR-T Conundrum: A Shared Target Problem
Dr. John F. DiPersio, MD, PhD, the Virginia E. & Sam J. Golman Professor of Medicine at WashU Medicine and the study’s corresponding author, elaborated on the significance of this gene-editing approach. He explained that it directly addresses a major obstacle that has historically constrained the application of CAR-T cell therapy against specific blood cancers, notably acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). While CAR-T therapy has demonstrated remarkable success in treating other aggressive blood cancers, its effectiveness against AML and MDS has been considerably more limited.
The core of the problem lies in the nature of the cellular targets. Many proteins found on AML and MDS cancer cells are also present on healthy myeloid cells, including the donor stem cells crucial for transplantation. When CAR-T cells are engineered to target one of these shared proteins, they risk inadvertently destroying these essential healthy blood stem cells alongside the cancerous ones. This collateral damage can trigger a severe and potentially life-threatening inflammatory response, a condition known as cytokine release syndrome. Furthermore, the therapeutic efficacy of the CAR-T treatment itself can be compromised, as a significant portion of the engineered immune cells are diverted to attacking healthy targets instead of concentrating their efforts on eradicating the malignant cells.
The conceptual foundation for this ingenious solution was first articulated by Dr. Miriam Y. Kim, MD, 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 the DiPersio lab. Her subsequent establishment as an independent investigator within the WashU Medicine Division of Oncology, while continuing to treat patients and conduct research at Siteman, underscores her pivotal role in this scientific journey.
Precision Engineering: Removing CD33 from Donor Stem Cells
The clinical trial implemented a sophisticated approach: patients diagnosed with AML and MDS received donor stem cells that had been meticulously genetically modified to eliminate a specific protein known as CD33. The strategic objective was to cultivate a population of healthy blood cells that would be rendered impervious to therapies specifically designed to target CD33.
"We are extremely encouraged by the results of this study, which demonstrate that a CD33-deleted stem cell transplant exhibits outcomes comparable to standard stem cell transplantation," stated Dr. DiPersio, who also leads WashU Medicine’s Center for Gene and Cellular Immunotherapy. "Looking ahead, our hope is to integrate this innovation with CD33-targeted immunotherapies, such as CAR-T cells, thereby enhancing treatment options for patients grappling with these particularly aggressive blood cancers."
Further bolstering this optimism, Dr. DiPersio and his research collaborators have documented a compelling single-case study. This case involved a patient with high-risk AML who underwent a CD33-deleted stem cell transplant. When the cancer unfortunately relapsed, the patient was subsequently treated with CD33-targeted CAR-T cells, 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 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 successfully restored, and all of the patient’s blood cells were confirmed to lack CD33. This definitive finding provided compelling evidence that the genetically engineered donor cells had successfully integrated and proliferated within the patient’s bone marrow. Dr. DiPersio served as the senior author on this additional study, published in October 2025 in JCO Precision Oncology.
Shielding Healthy Blood Cells: The CD33 Advantage
The choice of CD33 as the target protein for this innovative strategy is strategic and well-founded. CD33 is primarily expressed on blood-forming cells, and importantly, it is not found on other vital tissues within the body. Furthermore, scientific evidence suggests that CD33 is not essential for the normal functioning of blood stem cells. Individuals born with a genetic deficiency of CD33 have not exhibited any associated health problems, further validating its suitability as a target for selective elimination.
The underlying principle is elegantly simple yet profoundly impactful. Following a successful transplant with CD33-deleted stem cells, any remaining cells that still express CD33 are likely to be cancerous. Consequently, a CAR-T therapy or another immunotherapy specifically designed to target CD33 can then be administered. This targeted approach would enable the therapy to effectively attack and destroy the cancer cells while leaving the healthy donor-derived blood cells, which are now devoid of CD33, unharmed.
The phase 1/2 multicenter trial enrolled a cohort 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 sophisticated modification using CRISPR gene-editing technology to precisely remove the CD33 protein. The resulting product, a population of CD33-deleted stem cells, has been designated by the developer, Vor Biopharma, as tremtelectogene empogeditemcel (trem-cel). Vor Biopharma, the biotechnology company that developed this novel cellular therapy, provided funding for the study.
Testing the CD33-Targeted Therapeutic Approach
To rigorously assess the ability of the gene-edited stem cells to withstand a therapy directed at CD33, participants in the trial also received a post-transplantation maintenance treatment. This maintenance therapy 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 designed to recognize CD33 and deliver a potent anti-cancer drug 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 under investigation in clinical trials for CD33-positive MDS. While this antibody-drug conjugate can play a role 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.
Successful Engraftment of Gene-Edited Cells
A critical outcome of the trial was the successful engraftment of the transplanted stem cells. All 30 participating patients achieved engraftment by day 28 post-transplantation. This milestone signifies that the donor stem cells had successfully migrated to the bone marrow and commenced the vital process of producing new blood cells. Some patients reached this crucial stage even sooner, with platelet production returning to normal levels by an average of day 16. These recovery timelines were notably consistent with those typically observed in patients undergoing standard stem cell transplantation.
The average survival rate observed in the trial was just over 14 months. Nineteen of the patients received at least one cycle of gemtuzumab ozogamicin as part of a carefully designed dose-escalation protocol. This protocol was instrumental in allowing researchers to identify a recommended therapeutic dose for the maintenance therapy. Across the various dose levels administered, patients were able to maintain their blood cell counts. This 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 a common consequence when gemtuzumab ozogamicin is administered following a conventional stem cell transplant.
Side Effect Profile: Similar to Standard Transplants
The side effects experienced by patients during the trial were generally comparable to those associated with standard stem cell transplantation. These included common complications such as anemia, low platelet counts, fever, infections, and graft-versus-host disease (GVHD). GVHD is a serious complication where the donor’s immune cells (the graft) recognize the recipient’s body (the host) as foreign and initiate an attack on healthy tissues.
During the course of the study, 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. These complications included instances of kidney failure, liver toxicity, and sepsis, a life-threatening systemic inflammatory response to infection.
Future Implications: A New Frontier in Blood Cancer Therapy
Dr. DiPersio emphasized that the findings from this trial provide a robust foundation for the development of future treatment strategies. The ultimate goal is to create a synergistic approach that combines CD33-deleted stem cell transplantation with CD33-targeted immunotherapies. This powerful combination would empower physicians to more aggressively target and eliminate cancer cells without inadvertently jeopardizing the healthy donor cells that are indispensable for reconstituting the patient’s blood system.
The implications of this research are far-reaching. By enabling the safe and effective use of targeted therapies like CAR-T cells or antibody-drug conjugates against cancers that express CD33, this gene-editing technique offers a renewed sense of hope for patients with limited treatment options. It represents a significant step forward in the ongoing battle against some of the most challenging and life-threatening hematological malignancies, potentially transforming the landscape of care for these vulnerable patient populations. The successful engraftment and sustained blood cell production in the face of CD33-targeted therapy underscore the remarkable precision and efficacy of this genetic modification. This breakthrough not only addresses a critical unmet need in current treatment paradigms but also opens avenues for further research into targeting other shared antigens in different hematological malignancies.
The work was supported by Vor Biopharma. Several co-authors of the study were employees of Vor Biopharma at the time the research was conducted, highlighting the collaborative nature of translational research between academic institutions and industry partners. This partnership has been instrumental in translating complex scientific discoveries from the laboratory bench to the patient bedside, offering tangible benefits to those facing devastating diseases.
