For some of the most aggressive blood cancers, a stem cell transplant may be the only treatment with the potential to cure the disease. Still, cancers can recur after transplant, leaving doctors with limited options.
A new clinical trial led by researchers at Washington University School of Medicine in St. Louis suggests that genetically modifying donor stem cells before transplant could make follow-up cancer treatments safer and potentially more effective. The strategy removes a specific protein from the donor cells so that therapies targeting that protein can attack the cancer without affecting healthy transplanted cells.
The study was conducted at Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine, and 14 other sites in the U.S. and Canada. The results were published in Nature medicine.
A great challenge for CAR-T therapy
According to corresponding author John F. DiPersio, MD, PhD, Virginia E. and Sam J. Golman Professor of Medicine at WashU Medicine, the gene-editing approach could help overcome a major hurdle that has limited CAR-T cell therapy in certain blood cancers.
CAR-T therapy has been shown to be very effective against some aggressive blood cancers, but has not worked as well against diseases such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).
The problem, DiPersio explained, is that many proteins found in AML and MDS cancer cells also appear in healthy myeloid cells, including donor stem cells used in transplants. If CAR-T cells are programmed to attack one of those shared proteins, they can destroy healthy blood stem cells along with the cancer.
That damage can trigger a dangerous inflammatory response. It can also weaken the cancer treatment itself because a large number of CAR-T cells end up attacking healthy targets instead of focusing on malignant cells.
The underlying idea to avoid this problem was first described by Miriam Y. Kim, MD, now an assistant professor of medicine at WashU Medicine. Kim began research as a postdoctoral researcher at the University of Pennsylvania and continued it in the DiPersio laboratory before becoming an independent researcher in the WashU Medicine Oncology Division. She treats patients at Siteman and is also a research fellow there.
Extraction of CD33 from healthy stem cells
In the clinical trial, patients with AML and MDS received donor stem cells that had been genetically modified to remove a protein called CD33. The goal was to create healthy blood cells that were no longer vulnerable to treatments designed to target CD33.
“We are encouraged by the results of this study showing that a CD33-deleted stem cell transplant closely resembles the results of a standard stem cell transplant,” said DiPersio, who also directs WashU Medicine’s Center for Genetic and Cellular Immunotherapy. “In the future, we are hopeful that we can combine this with immunotherapies targeting CD33, such as CAR-T cells, and improve treatment options for patients with these very aggressive blood cancers.”
DiPersio and colleagues also reported a unique case involving a patient with high-risk acute myeloid leukemia who received a CD33-deleted stem cell transplant. When the cancer recurred, the patient was treated with CD33-targeting CAR T cells made from T cells provided by the same donor who provided the original stem cells.
The patient, who had one of the most aggressive forms of AML, went into complete remission and remained cancer-free more than a year after CAR-T treatment. Normal blood cell production also returned and all of the patient’s blood cells lacked CD33. That finding indicated that the genetically modified donor cells had successfully established themselves in the bone marrow. DiPersio is the lead author of that study, which was published in October 2025 in JCO Precision Oncology.
Protect healthy blood cells
CD33 is an attractive target for this strategy because the protein is found only in blood-forming cells and not in other tissues. Evidence also suggests that CD33 is not necessary for normal blood stem cell function, as people born without the protein do not appear to have related health problems.
After a successful transplant with CD33-deleted stem cells, the theory is that any cells still carrying CD33 should be primarily cancer cells. A CAR-T therapy or other immunotherapy targeting CD33 could attack those cancer cells and leave healthy donor-derived blood cells alone.
The multicenter phase 1/2 trial enrolled 30 adults with AML or MDS who were considered at high risk for relapse. Before transplant, the donor stem cells were modified with CRISPR gene editing to delete CD33.
The resulting CD33-deleted stem cell product is called tremtelectogene empogeditemcel (trem-cel). It was developed by Vor Biopharma, which funded the study.
Testing a cancer treatment targeting CD33
To test whether the edited stem cells could resist CD33-targeting therapy, patients also received maintenance treatment after transplant.
The drug, gemtuzumab ozogamicin, is not a CAR-T therapy targeting CD33. Instead, it is an engineered antibody that recognizes CD33 and delivers an anti-cancer drug directly to the cells carrying the protein.
Gemtuzumab ozogamicin is approved by the Food and Drug Administration for CD33-positive AML and is being tested in clinical trials for CD33-positive MDS. Although treatment can help prevent relapse, its usefulness is limited by side effects that include liver toxicity and damage to healthy blood cells. Patients can develop dangerously low levels of white blood cells, red blood cells, and platelets.
Gene-edited cells successfully grafted
All 30 patients achieved engraftment on day 28, meaning the transplanted stem cells reached the bone marrow and began producing blood cells. Some patients reached that milestone sooner, while platelet production returned on average by day 16.
Those recovery times were similar to those typically seen with standard stem cell transplant.
The average survival in the trial was just over 14 months. Nineteen patients received at least one cycle of gemtuzumab ozogamicin as part of a dose escalation protocol, allowing researchers to identify a recommended dose.
Across the different doses, patients maintained their blood cell counts. The finding suggests that the edited gene transplant protected them from the severe drops in blood cells that often occur when this maintenance therapy is used after a conventional stem cell transplant.
Side effects remained similar to standard transplants
The side effects observed during treatment were very similar to those associated with standard stem cell transplantation. They included anemia, low platelet counts, fever, infections and graft-versus-host disease, in which donor cells attack the patient’s healthy tissues.
Seven patients died during the study. Four deaths were due to cancer progression, while three were related to transplant-related complications such as kidney failure, liver toxicity and sepsis.
DiPersio said the findings provide a basis for future treatments that combine transplantation of CD33-deleted stem cells with immunotherapies targeting CD33. The goal is to allow doctors to attack cancer cells more aggressively without simultaneously destroying healthy donor cells needed to rebuild the patient’s blood system.
This work was supported by Vor Biopharma. Several co-authors were employees of the company when the work was performed.