By Hendra Lukman 
For patients battling some of the most aggressive forms of blood cancers, a stem cell transplant has long represented the last bastion of hope, offering the potential for a cure where other treatments have faltered. However, the specter of cancer relapse following transplantation has cast a long shadow, leaving physicians with a dwindling arsenal of options. Now, a pivotal 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 can significantly enhance the safety and efficacy of subsequent cancer therapies. This innovative strategy involves the precise removal of a specific protein from donor cells, thereby enabling targeted therapies to attack cancer cells while meticulously sparing the essential, healthy transplanted cells.
The groundbreaking research, conducted across the Siteman Cancer Center at Barnes-Jewish Hospital and WashU Medicine, alongside 14 other esteemed institutions throughout 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 widespread application of CAR-T cell therapy in certain challenging blood cancers.
Addressing a Critical Bottleneck in CAR-T Therapy
"This gene editing approach has the potential to circumvent a major obstacle that has constrained the effectiveness of CAR-T cell therapy for specific blood cancers," stated corresponding author John F. DiPersio, MD, PhD, the Virginia E. & Sam J. Golman Professor of Medicine at WashU Medicine. CAR-T (Chimeric Antigen Receptor T-cell) therapy, a revolutionary form of immunotherapy where a patient’s own T cells are genetically engineered to recognize and attack cancer cells, has demonstrated remarkable success against certain hematologic malignancies. However, its impact has been less pronounced against aggressive diseases like acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
The crux of the challenge, as Dr. DiPersio explained, lies in the shared expression of certain proteins on both AML and MDS cancer cells and on healthy myeloid cells, including the crucial donor stem cells utilized in transplantation. When CAR-T cells are designed to target one of these common proteins, they risk indiscriminately destroying healthy blood stem cells alongside malignant ones. This collateral damage can trigger a severe and potentially life-threatening inflammatory response. Furthermore, it can dilute the therapeutic impact of the CAR-T therapy itself, as a significant portion of the engineered cells are diverted to attack harmless targets rather than concentrating their efforts on eradicating the cancer.
The foundational concept for this ingenious solution was first articulated by Miriam Y. Kim, MD, now an assistant professor of medicine at WashU Medicine. Dr. Kim initiated this line of research as a postdoctoral fellow at the University of Pennsylvania, continuing her work in the DiPersio lab before establishing her own independent research program within the WashU Medicine Division of Oncology. She actively treats patients at Siteman Cancer Center and contributes significantly as a research member there.
The Strategic Removal of CD33: Shielding Healthy Cells
The clinical trial meticulously involved patients diagnosed with AML and MDS who received donor stem cells that had been genetically modified to eliminate a protein known as CD33. The strategic objective was to cultivate a population of healthy blood cells that would be impervious to therapies specifically designed to target CD33.
"We are highly encouraged by the outcomes of this study, which demonstrate that a CD33-deleted stem cell transplant yields results remarkably similar to those of standard stem cell transplantation," Dr. DiPersio, who also serves as the director of WashU Medicine’s Center for Gene and Cellular Immunotherapy, commented. "Looking ahead, we are optimistic about the potential to integrate this approach with CD33-targeted immunotherapies, such as CAR-T cells, thereby expanding and improving treatment paradigms for individuals afflicted with these particularly aggressive blood cancers."
In a compelling testament to the potential of this technology, Dr. DiPersio and his colleagues have also detailed a single case study involving a patient with high-risk AML. This individual underwent a CD33-deleted stem cell transplant. When the cancer unfortunately recurred, the patient was subsequently treated with CD33-targeted CAR-T cells derived from the same donor who had provided the initial stem cells. The 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 lack CD33. This critical finding provided definitive evidence that the genetically engineered donor cells had successfully engrafted and established themselves within the bone marrow. Dr. DiPersio was the senior author of this case study, which was published in October 2025 in the journal JCO Precision Oncology.
Unveiling the Rationale: CD33 as a Prime Target
CD33 emerges as an exceptionally suitable target for this innovative strategy due to its specific expression. The protein is found predominantly on blood-forming cells, with minimal presence on other tissues. Furthermore, existing evidence suggests that CD33 is not essential for the normal functioning of blood stem cells. Individuals born without this protein do not appear to experience any associated health complications, underscoring its dispensability for overall health.
The underlying hypothesis is that following a successful transplant with CD33-deleted stem cells, any remaining cells that still express CD33 are likely to be cancer cells. Consequently, a CAR-T therapy or another CD33-targeting immunotherapy could be deployed to specifically eradicate these malignant cells, while leaving the healthy donor-derived blood cells unharmed and allowing them to repopulate the patient’s blood system.
The Clinical Trial: A Phase 1/2 Multicenter Study
The phase 1/2 multicenter trial enrolled a cohort of 30 adult patients diagnosed with AML or MDS who were identified as being at a high risk of disease relapse. Prior to transplantation, the donor stem cells underwent precise modification using CRISPR gene editing technology to effectively excise CD33. The resulting genetically modified product, characterized by the absence of CD33 on its surface, is known as tremtelectogene empogeditemcel (trem-cel). This novel therapeutic agent was developed by Vor Biopharma, which also provided the funding for the study, underscoring the significant investment and interest in this pioneering approach.
Testing the Resilience: CD33-Targeted Cancer Treatment
To rigorously assess the ability of the gene-edited stem cells to withstand therapies directed at CD33, participants in the trial also received a maintenance treatment following transplantation. The drug employed for this purpose was gemtuzumab ozogamicin. It is important to note that this is not a CAR-T therapy but rather an engineered antibody designed to recognize CD33 and deliver a potent anti-cancer drug directly to cells that express the target 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 disease recurrence, its clinical utility has been historically hampered by significant side effects. These can include liver toxicity and damage to healthy blood cells, leading to dangerously low counts of white blood cells, red blood cells, and platelets.
Evidence of Successful Engraftment: A Promising Sign
A critical milestone in any stem cell transplant is engraftment, the process by which the transplanted stem cells successfully migrate to the bone marrow and begin producing new blood cells. In this trial, all 30 patients achieved engraftment by day 28 post-transplantation, a timeline that is comparable to what is typically observed with standard stem cell transplantation protocols. Furthermore, platelet production, another key indicator of hematopoietic recovery, returned on average by day 16. These recovery metrics provide strong reassurance that the gene-edited stem cells are functioning as intended and are capable of reconstituting the patient’s blood system.
The average survival observed in the trial was just over 14 months. Notably, 19 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 recommended safe and effective dose. Across the various dose levels, patients were able to maintain their blood cell counts. This finding is particularly significant, suggesting that the gene-edited transplant effectively shielded them from the profound and often severe drops in blood cell counts that are commonly encountered when this maintenance therapy is administered following a conventional stem cell transplant.
Safety Profile: A Balancing Act
The adverse events reported during the course of the treatment were broadly similar to those associated with standard stem cell transplantation. These included expected complications such as anemia, low platelet counts, fever, infections, and graft-versus-host disease (GVHD), a serious condition where the donor cells mount an immune attack against the recipient’s healthy tissues.
During the study period, seven patients succumbed to their illness. Of these deaths, four were attributed to the progression of their underlying cancer, a testament to the aggressive nature of the diseases being treated. The remaining three deaths were linked to transplant-related complications, including kidney failure, liver toxicity, and sepsis, highlighting the inherent risks associated with intensive stem cell transplantation.
Future Implications: A New Era in Blood Cancer Treatment
Dr. DiPersio emphasized that these findings lay a crucial foundation for the development of future therapeutic strategies that aim to synergistically combine CD33-deleted stem cell transplantation with CD33-targeted immunotherapies. The ultimate goal is to empower physicians to more aggressively target and eradicate cancer cells without inadvertently compromising the vital donor cells required to rebuild the patient’s compromised blood system. This innovative approach represents a significant step forward in the ongoing battle against some of the most formidable blood cancers, offering a glimmer of renewed hope for patients and their families. The successful engraftment and apparent protection of healthy blood cells in the face of CD33-targeted therapy mark a pivotal moment in the evolution of cancer treatment, potentially ushering in a new era of precision medicine for hematologic malignancies.
