By Hendra Lukman 
For patients battling some of the most aggressive forms of blood cancer, a stem cell transplant represents a critical lifeline, often offering the only potential for a cure. However, the specter of cancer recurrence post-transplant looms large, frequently leaving physicians with a challenging landscape of limited follow-up treatment options. Now, a groundbreaking clinical trial spearheaded by researchers at the Washington University School of Medicine in St. Louis is illuminating a path toward safer and potentially more effective post-transplant therapies. This innovative strategy involves genetically modifying donor stem cells before transplantation, specifically by removing a protein target that is also present on cancer cells. This crucial alteration aims to enable subsequent cancer treatments to precisely target malignant cells while sparing the vital, newly transplanted healthy cells.
The findings, published in the esteemed journal Nature Medicine, stem from a multicenter clinical trial 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. This collaborative effort represents a significant stride in the ongoing battle against formidable hematologic malignancies.
Overcoming a Critical Hurdle in CAR-T Therapy
The development of chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of certain blood cancers, demonstrating remarkable efficacy. However, its application has been notably constrained in diseases such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). According to Dr. John F. DiPersio, MD, PhD, the Virginia E. & Sam J. Golman Professor of Medicine at WashU Medicine and the study’s corresponding author, the gene-editing approach explored in this trial directly addresses a fundamental obstacle hindering CAR-T therapy’s broader success in these challenging cancers.
The crux of the problem, as explained by Dr. DiPersio, lies in the shared expression of certain proteins on both AML and MDS cancer cells and healthy myeloid cells, including the crucial donor stem cells utilized in transplantation. When CAR-T cells are engineered to target such a shared protein, they inevitably strike healthy blood stem cells alongside the cancerous ones. This collateral damage can precipitate a dangerous inflammatory cascade within the patient’s body. Furthermore, it can dilute the potency of the cancer treatment itself, as a substantial proportion of the CAR-T cells expend their energy attacking benign targets instead of concentrating their full force on the malignant cells.
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 initiated this research during her postdoctoral fellowship at the University of Pennsylvania and continued 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 is a dedicated research member there, bringing a unique blend of clinical expertise and pioneering research.
The Precision Strike: Removing CD33 from Donor Stem Cells
In the conducted clinical trial, patients diagnosed with AML and MDS received donor stem cells that had undergone precise genetic modification to eliminate the presence of a specific 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 greatly encouraged by the results of this study, which demonstrate that a CD33-deleted stem cell transplant exhibits outcomes comparable to those of standard stem cell transplantation," stated Dr. DiPersio, who also holds the directorship of WashU Medicine’s Center for Gene and Cellular Immunotherapy. "Looking ahead, we are optimistic that we will be able to integrate this approach with CD33-targeted immunotherapies, such as CAR-T cells, thereby enhancing treatment paradigms for patients afflicted with these particularly aggressive blood cancers."
Dr. DiPersio and his research team have also documented a compelling single-case study involving a patient with high-risk AML who underwent a CD33-deleted stem cell transplant. When the patient’s cancer unfortunately recurred, a subsequent treatment involved CD33-targeted CAR-T cells, meticulously derived from T cells provided by the same donor who had supplied the original stem cells. 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 therapy. Crucially, normal blood cell production was restored, and all of the patient’s blood cells were found to be CD33-negative, a definitive indicator that the genetically engineered donor cells had successfully integrated and proliferated within the bone marrow. This significant case study was published in October 2025 in JCO Precision Oncology, with Dr. DiPersio serving as the senior author.
Shielding Healthy Blood Cells: The Rationale Behind CD33 Deletion
CD33 emerges as an ideal target for this innovative strategy due to its specific expression pattern. The protein is predominantly found on blood-forming cells, with minimal or no presence on other bodily tissues. Furthermore, emerging scientific evidence suggests that CD33 is not essential for the normal functioning of blood stem cells. Individuals born with a genetic deficiency of CD33 do not appear to experience any significant health complications, further validating its removal as a safe therapeutic maneuver.
The underlying principle of this approach posits that following a successful transplant with CD33-deleted stem cells, any remaining cells in the body expressing CD33 would likely be malignant cancer cells. Consequently, a CAR-T therapy or another form of immunotherapy specifically designed to target CD33 could then be administered to effectively eliminate these cancer cells, leaving the healthy, donor-derived blood cells untouched and allowing them to rebuild the patient’s blood system.
The Clinical Trial: A Phased Approach to Innovation
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 relapse. Prior to their transplantation, the donor stem cells underwent modification using CRISPR gene-editing technology to excise the CD33 protein. The resulting genetically engineered stem cell product has been designated tremtelectogene empogeditemcel, or trem-cel, and was developed by Vor Biopharma, the company that also provided funding for the study.
Testing the CD33-Targeted Cancer Treatment Post-Transplant
To rigorously assess the ability of the gene-edited stem cells to withstand a therapy directed at CD33, patients in the trial also received a maintenance treatment following their transplantation. The drug administered was gemtuzumab ozogamicin, an antibody-drug conjugate that, while not a CAR-T therapy, is specifically engineered to recognize CD33. Upon binding to CD33-positive cells, it delivers a potent anti-cancer drug directly to the malignant cells.
Gemtuzumab ozogamicin has already 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 therapeutic agent can play a role in preventing cancer relapse, its clinical utility has been historically hampered by significant side effects, including hepatotoxicity and damage to healthy blood cells, often leading to dangerously low counts of white blood cells, red blood cells, and platelets.
Successful Engraftment of Gene-Edited Cells
A critical benchmark of any stem cell transplant is successful engraftment – the point at which the transplanted stem cells successfully integrate into the patient’s bone marrow and begin the process of producing new blood cells. In this trial, all 30 patients achieved engraftment by day 28 post-transplantation. Some patients reached this vital milestone even sooner, and on average, platelet production was restored by day 16. These recovery timelines are notably consistent with those observed in standard stem cell transplantation protocols, indicating that the genetic modification did not impede the fundamental engraftment process.
The average survival observed in the trial was just over 14 months. A significant portion of the cohort, nineteen patients, received at least one cycle of gemtuzumab ozogamicin as part of a carefully designed dose-escalation protocol. This phased approach allowed researchers to meticulously identify a safe and effective recommended dose of the maintenance therapy. Across the various dose levels, patients maintained their blood cell counts, a crucial finding that suggests the gene-edited transplant effectively shielded them from the severe, often debilitating, drops in blood cell counts that are a common consequence of using gemtuzumab ozogamicin after a conventional stem cell transplant.
Side Effect Profile: Familiar Territory
The adverse events experienced by patients during the trial were largely consistent with those typically associated with standard stem cell transplantation. These included common complications such as anemia, reduced platelet counts, fever, infections, and graft-versus-host disease (GVHD), a serious condition where the donor’s immune cells mistakenly attack the recipient’s healthy tissues.
During the study period, seven patients succumbed to their illness. Of these, four 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.
The Future of Blood Cancer Treatment: A Synergistic Approach
Dr. DiPersio articulated that the findings from this study provide a robust foundation for the development of future treatment strategies that will synergistically combine CD33-deleted stem cell transplantation with CD33-targeted immunotherapies. The ultimate aim is to empower clinicians to confront cancer cells with increased aggression, while simultaneously safeguarding the vital donor cells essential for reconstituting the patient’s blood system.
This pioneering research was made possible through the support of Vor Biopharma. It is important to note that several co-authors of the study were employees of Vor Biopharma at the time the research was conducted, highlighting the collaborative nature of this scientific endeavor. The implications of this trial extend beyond the immediate cohort, offering a beacon of hope and a tangible pathway toward improved outcomes for individuals facing the daunting challenges of aggressive blood cancers. The ability to precisely target cancer while preserving healthy, transplanted cells marks a significant evolution in the quest for definitive cures.
