By Hendra Lukman 
For patients battling some of the most aggressive forms of blood cancer, a stem cell transplant has long represented the last bastion of hope, offering the potential for a cure where other treatments have failed. However, the specter of relapse looms large, as cancers can return even after a successful transplant, often leaving physicians with few recourse options. Now, a groundbreaking clinical trial spearheaded by researchers at the Washington University School of Medicine in St. Louis is illuminating a new path forward, suggesting that genetically modifying donor stem cells before transplantation could usher in an era of safer and significantly more effective follow-up cancer treatments. This innovative strategy involves the precise removal of a specific protein from donor cells, enabling targeted therapies to eradicate cancer cells while leaving the crucial, healthy transplanted cells unharmed.
The pivotal 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, has yielded results published in the prestigious journal Nature Medicine. This advancement holds particular promise for overcoming a significant hurdle that has historically limited the efficacy of CAR-T cell therapy in specific blood cancers, according to corresponding author John F. DiPersio, MD, PhD, the Virginia E. & Sam J. Golman Professor of Medicine at WashU Medicine.
Addressing the CAR-T Therapy Conundrum
While CAR-T (Chimeric Antigen Receptor T-cell) therapy has demonstrated remarkable success against certain aggressive blood cancers, its impact has been less pronounced in diseases such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The crux of the challenge, as explained by Dr. DiPersio, lies in the shared molecular landscape of these cancers. Many proteins found on AML and MDS cancer cells are also present on healthy myeloid cells, including the very donor stem cells vital for transplantation. Consequently, if CAR-T cells are engineered to target one of these common proteins, they risk indiscriminately destroying healthy blood stem cells alongside malignant ones.
This collateral damage can trigger a dangerous inflammatory cascade within the patient’s body. Moreover, it can dilute the potency of the cancer treatment itself, as a substantial portion of the engineered CAR-T cells are diverted to attacking benign targets rather than concentrating their efforts on eradicating cancerous cells. The conceptual foundation for circumventing this critical limitation was initially articulated by Miriam Y. Kim, MD, now an assistant professor of medicine at WashU Medicine. Dr. Kim embarked on this research as a postdoctoral fellow at the University of Pennsylvania, continuing her work in the DiPersio laboratory before establishing herself as an independent investigator within the WashU Medicine Division of Oncology. She actively treats patients at Siteman Cancer Center and is an integral research member there.
Precision Engineering: Removing CD33 from Healthy Stem Cells
The clinical trial implemented a novel approach: patients diagnosed with AML and MDS received donor stem cells that had been genetically modified to eliminate a protein known as CD33. The objective was to cultivate a population of healthy blood cells that would be rendered invisible to therapies specifically 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."
Further underscoring the potential of this approach, Dr. DiPersio and his colleagues reported on a single, highly complex case involving a patient with high-risk AML. This individual underwent a CD33-deleted stem cell transplant. When the cancer recurred, the patient was subsequently treated with CD33-targeted CAR-T cells, meticulously derived 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 restored, and all of the patient’s blood cells were found to be devoid of CD33. This vital observation served as definitive evidence that the genetically engineered donor cells had successfully integrated and proliferated within the patient’s bone marrow. Dr. DiPersio is the senior author of this case study, which was published in October 2025 in JCO Precision Oncology.
Shielding Healthy Blood Cells: The CD33 Advantage
CD33 emerged as an ideal target for this sophisticated strategy due to its specific expression pattern. The protein is predominantly found on blood-forming cells and is largely absent from 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 complications, reinforcing its safety as a target for elimination.
The underlying principle of this innovative therapy is that following a successful transplant with CD33-deleted stem cells, any cells that still express CD33 are likely to be cancerous. Subsequently, a CD33-targeted CAR-T therapy or another form of immunotherapy could be deployed to specifically attack these malignant cells, leaving the healthy donor-derived blood cells untouched and allowing them to repopulate the patient’s blood system.
The phase 1/2 multicenter trial was designed to evaluate this strategy in 30 adult patients diagnosed with AML or MDS who were deemed to be at high risk of disease relapse. Prior to transplantation, donor stem cells underwent modification using CRISPR gene editing technology to precisely remove the CD33 protein. The resulting product, the CD33-deleted stem cell therapy, is known by its investigational name, tremtelectogene empogeditemcel (trem-cel). This pioneering therapy was developed by Vor Biopharma, which also provided the funding for the clinical study.
Testing a CD33-Targeted Cancer Treatment in Practice
To rigorously assess the resilience of the gene-edited stem cells against therapies directed at CD33, participants in the trial also received a maintenance treatment following their transplant. 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 directly deliver an anti-cancer agent to cells bearing 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 treatment has shown promise in preventing relapse, its clinical utility has been somewhat constrained by significant side effects, including liver toxicity and damage to healthy blood cells, which can manifest as dangerously low levels of white blood cells, red blood cells, and platelets.
Evidence of Successful Engraftment and Therapeutic Potential
A critical milestone for any stem cell transplant is engraftment, the process by which transplanted stem cells migrate to the bone marrow and begin producing new blood cells. In this trial, all 30 patients achieved successful engraftment by day 28 post-transplant. Notably, some patients reached this crucial stage even earlier. Furthermore, platelet production, a key indicator of hematopoietic recovery, returned by day 16 on average. These recovery timelines were found to be comparable to those typically observed in patients undergoing standard stem cell transplantation, suggesting that the gene-editing process did not impede the fundamental engraftment process.
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 carefully orchestrated dose-escalation protocol. This phased approach allowed researchers to meticulously 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 is particularly significant, as it strongly suggests that the gene-edited transplant effectively shielded them from the severe drops in blood cell production that are a common and often debilitating consequence of using this maintenance therapy following a conventional stem cell transplant.
Side Effect Profile and Future Directions
The spectrum of side effects encountered during the trial was broadly consistent with those typically 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 immune cells attack the recipient’s healthy tissues.
During the study period, seven patients passed away. 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 scientific foundation for the development of future therapeutic strategies that aim to synergistically combine CD33-deleted stem cell transplantation with CD33-targeted immunotherapies. The overarching goal of this integrated approach is to empower clinicians to attack cancer cells with greater intensity and precision, while simultaneously safeguarding the essential healthy donor cells that are indispensable for rebuilding the patient’s compromised blood system. This research was supported by Vor Biopharma, with several co-authors being employees of the company at the time the work was conducted.
Broader Implications and the Road Ahead
The success of this trial marks a significant stride in the ongoing battle against aggressive blood cancers. By demonstrating the feasibility and safety of genetically modifying donor stem cells to resist targeted therapies, researchers have opened a critical new avenue for treatment. This strategy has the potential to broaden the applicability of potent immunotherapies like CAR-T cells to diseases like AML and MDS, which have historically been more challenging to treat with these advanced modalities.
The ability to "cloak" healthy transplanted cells from targeted therapies offers a paradigm shift. It allows for more aggressive treatment regimens that might otherwise be too toxic. This could lead to improved remission rates and longer survival for patients with few other options. Furthermore, the study’s findings on the successful engraftment and sustained blood cell production, even in conjunction with post-transplant therapy, suggest that the genetically modified cells are not only safe but also functionally robust.
Looking forward, the clinical development of tremtelectogene empogeditemcel (trem-cel) and similar gene-edited cell therapies will likely focus on further refining dosing strategies, expanding patient populations, and potentially combining these approaches with other novel immunotherapies. The long-term implications of this research extend beyond immediate patient outcomes, offering a glimpse into a future where personalized medicine, driven by sophisticated gene editing technologies, can fundamentally alter the landscape of cancer treatment, transforming previously intractable diseases into manageable, and potentially curable, conditions. The ongoing collaboration between academic institutions and biotechnology companies, as exemplified by this study, is crucial for translating these complex scientific breakthroughs into tangible clinical benefits for patients worldwide.
