By Hendra Lukman 
For individuals battling some of the most aggressive forms of blood cancers, a stem cell transplant remains the most promising, and often the only, curative option. However, the specter of cancer recurrence post-transplant frequently leaves physicians with a dwindling arsenal of treatment choices. Now, a groundbreaking clinical trial spearheaded by researchers at the Washington University School of Medicine in St. Louis is introducing a potentially transformative approach: genetically modifying donor stem cells before transplantation. This innovative strategy aims to enhance the safety and efficacy of subsequent cancer therapies by meticulously removing a specific protein from the donor cells, thereby enabling targeted treatments to eliminate cancer while safeguarding the newly engrafted healthy cells.
The findings from this pivotal study, conducted at the Siteman Cancer Center – a collaborative effort between Barnes-Jewish Hospital and WashU Medicine – alongside 14 other leading research institutions across the United States and Canada, have been published in the esteemed journal Nature Medicine. This research represents a significant leap forward in the fight against recalcitrant hematologic malignancies.
Overcoming a Critical Hurdle in CAR-T Therapy
Dr. John F. DiPersio, the Virginia E. & Sam J. Golman Professor of Medicine at WashU Medicine and the corresponding author of the study, elucidated how this gene-editing technique is poised to address a formidable challenge that has historically curtailed the effectiveness of Chimeric Antigen Receptor T-cell (CAR-T) therapy in certain blood cancers.
CAR-T therapy, a revolutionary form of immunotherapy, has demonstrated remarkable success against a spectrum of aggressive blood cancers. However, its application has been less impactful against diseases such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The core issue, as explained by Dr. DiPersio, lies in the expression of certain proteins on both cancer cells and healthy myeloid cells, including the crucial donor stem cells that form the foundation of a transplant. When CAR-T cells are engineered to target such a shared protein, they risk indiscriminately attacking and destroying healthy blood stem cells alongside malignant ones.
This collateral damage can trigger a dangerous systemic inflammatory response, known as cytokine release syndrome, and can also dilute the potency of the cancer treatment itself. A significant portion of the therapeutic CAR-T cells may end up targeting healthy, intended-to-be-repopulated cells, diverting their destructive power away from the cancer.
The conceptual framework for circumventing this critical limitation was initially conceptualized by Dr. Miriam Y. Kim, now an assistant professor of medicine at WashU Medicine. Dr. Kim’s foundational research on this subject began during her postdoctoral fellowship at the University of Pennsylvania. She continued this work within Dr. DiPersio’s laboratory before establishing herself as an independent investigator in the Division of Oncology at WashU Medicine. Dr. Kim also actively participates in patient care at Siteman Cancer Center and contributes significantly to its research endeavors.
Precision Engineering: The Removal of CD33 from Healthy Stem Cells
In the meticulously designed clinical trial, patients diagnosed with AML and MDS received donor stem cells that had undergone sophisticated genetic modification to excise a specific protein known as CD33. The overarching objective was to cultivate a population of healthy blood cells that would be rendered invisible to therapies specifically designed to target CD33.
"We are profoundly encouraged by the results of this study, which demonstrate that a CD33-deleted stem cell transplant yields outcomes remarkably similar to those observed with standard stem cell transplantation," stated Dr. DiPersio, who also holds the directorship of WashU Medicine’s Center for Gene and Cellular Immunotherapy. "Looking ahead, our hope is to integrate this approach with CD33-targeted immunotherapies, such as CAR-T cells, thereby expanding and enhancing treatment options for patients afflicted with these particularly aggressive blood cancers."
Complementing the findings of the multicenter trial, Dr. DiPersio and his colleagues have also documented a compelling single-case study involving a patient with high-risk AML. This patient underwent a transplant with CD33-deleted donor stem cells. When the cancer unfortunately recurred, the patient was subsequently treated with CD33-targeted CAR-T cells, meticulously manufactured from T cells donated by the same individual who provided the original 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 therapy. Crucially, normal blood cell production was restored, and all of the patient’s blood cells were found to lack CD33. This critical observation provided definitive evidence that the genetically engineered donor cells had successfully integrated and were producing blood cells within the patient’s bone marrow. Dr. DiPersio is the senior author of this case study, which was published in October 2025 in the journal JCO Precision Oncology.
A Shield for Healthy Blood Cells: Targeting CD33
The protein CD33 presents an ideal target for this innovative strategy due to its specific presence on blood-forming cells, with a notable absence in other bodily tissues. Furthermore, emerging evidence suggests that CD33 is not indispensable for the normal functioning of blood stem cells. Individuals born without this protein do not appear to experience any associated health complications, further solidifying its suitability as a therapeutic target.
The underlying principle of this approach posits that following a successful transplant of CD33-deleted stem cells, any remaining cells expressing CD33 would predominantly be cancer cells. Consequently, a CAR-T therapy or other CD33-targeting immunotherapy could then be deployed to effectively eradicate these malignant cells while leaving the healthy donor-derived blood cells unharmed and intact.
The phase 1/2 multicenter trial enrolled a cohort of 30 adult patients diagnosed with AML or MDS, all of whom were identified as being at a high risk of disease relapse. Prior to transplantation, the donor stem cells were meticulously modified using CRISPR gene-editing technology to ensure the complete removal of CD33. The resulting genetically engineered product, the CD33-deleted stem cell formulation, has been designated by the developer, Vor Biopharma, as tremtelectogene empogeditemcel (trem-cel). Vor Biopharma was also the primary funder of this critical study.
Rigorous Testing of a CD33-Targeted Cancer Treatment
To rigorously assess the capacity of the edited stem cells to withstand a therapy specifically directed at CD33, participants in the trial were administered a maintenance treatment following their transplantation. This post-transplant regimen involved the use of gemtuzumab ozogamicin, an antibody-drug conjugate. Unlike CAR-T therapy, gemtuzumab ozogamicin is an engineered antibody that precisely recognizes CD33 and directly delivers a potent anti-cancer drug to cells expressing this 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 undergoing investigation in clinical trials for CD33-positive MDS. While this treatment can be instrumental in preventing relapse, its clinical utility has been historically constrained by significant side effects, including liver toxicity and damage to healthy blood cells, leading to dangerously low levels of white blood cells, red blood cells, and platelets.
Evidence of Successful Engraftment in Gene-Edited Cells
A critical early milestone was the successful engraftment of transplanted stem cells in all 30 patients by day 28 of the study. Engraftment signifies that the transplanted stem cells have successfully migrated to the bone marrow and have commenced the production of new blood cells. Some patients achieved this vital milestone even sooner. Furthermore, platelet production, a key indicator of bone marrow recovery, returned by day 16 on average. These recovery timelines were notably comparable to those typically observed in patients undergoing conventional, non-genetically modified stem cell transplantation.
The average survival observed in the trial extended to 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 phased approach enabled researchers to meticulously identify a safe and effective recommended dosage for the maintenance therapy. Across the various dosage levels administered, patients were able to maintain their blood cell counts. This crucial finding strongly suggests that the genetically edited stem cell transplant effectively shielded them from the severe drops in blood cell counts that are often a debilitating consequence of using this maintenance therapy following a conventional stem cell transplant.
Side Effect Profile Remains Comparable to Standard Transplants
Importantly, the side effects encountered during the treatment period were generally consistent with those typically associated with standard stem cell transplantation. These included common complications such as anemia, low platelet counts, fever, infections, and graft-versus-host disease (GVHD), a serious condition where the donor immune cells recognize the recipient’s body as foreign and attack healthy tissues.
Tragically, seven patients succumbed to their illnesses during the study period. Four of these deaths were directly 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 lay a robust foundation for the development of future therapeutic strategies that synergistically combine CD33-deleted stem cell transplantation with advanced CD33-targeted immunotherapies. The ultimate goal is to empower clinicians to aggressively combat cancer cells while simultaneously preserving the integrity of the healthy donor cells essential for reconstituting the patient’s blood system.
This research was generously supported by Vor Biopharma, with several co-authors holding employment with the company at the time the work was conducted, underscoring the collaborative nature of this scientific endeavor.
