CRISPR could help doctors attack blood cancer without destroying healthy cells

For some of the most aggressive blood cancers, a stem cell transplant may be the only treatment with the potential to cure the disease. Even so, cancers can return after transplantation, 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 transplantation could make follow-up cancer treatments safer and potentially more effective. The strategy removes a specific protein from donor cells so that therapies aimed at that protein can attack cancer while sparing 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 Major Challenge for CAR-T Therapy

According to corresponding author John F. DiPersio, MD, PhD, the Virginia E. & Sam J. Golman Professor of Medicine at WashU Medicine, the gene editing approach could help overcome a major obstacle that has limited CAR-T cell therapy in certain blood cancers.

CAR-T therapy has proved highly effective against some aggressive blood cancers, but it 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 on AML and MDS cancer cells also appear on healthy myeloid cells, including donor stem cells used in transplantation. If CAR-T cells are programmed to attack one of those shared proteins, they may destroy healthy blood stem cells along with the cancer.

That damage can trigger a dangerous inflammatory response. It may also weaken the cancer treatment itself because large numbers of CAR-T cells end up attacking healthy targets instead of concentrating on malignant cells.

The underlying idea for avoiding this problem was first described by Miriam Y. Kim, MD, now an assistant professor of medicine at WashU Medicine. Kim began the research as a postdoctoral researcher at the University of Pennsylvania and continued it in the DiPersio lab before becoming an independent investigator in the WashU Medicine Division of Oncology. She treats patients at Siteman and is also a research member there.

Removing 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 would no longer be vulnerable to treatments designed to attack 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," said DiPersio, who also directs 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."

DiPersio and his collaborators have also reported a single case involving a patient with high-risk AML who received a CD33-deleted stem cell transplant. When the cancer later returned, the patient was treated with CD33-targeted CAR-T cells made from T cells provided by the same donor who supplied the original stem cells.

The patient, who had one of the most aggressive forms of AML, entered complete remission and remained cancer-free more than one 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 engineered donor cells had successfully established themselves in the bone marrow. DiPersio is the senior author of that study, which was published in October 2025 in JCO Precision Oncology.

Shielding Healthy Blood Cells

CD33 is an attractive target for this strategy because the protein is found only on blood-forming cells and not on other tissues. Evidence also suggests that CD33 is not necessary for normal blood stem cell function, since 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 primarily be cancer cells. A CAR-T therapy or another immunotherapy targeting CD33 could then attack those cancer cells while leaving the healthy donor-derived blood cells alone.

The phase 1/2 multicenter trial enrolled 30 adults with AML or MDS who were considered at high risk of relapse. Before transplantation, donor stem cells were modified with CRISPR gene editing to remove 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 CD33-Targeted Cancer Treatment

To test whether the edited stem cells could withstand a therapy directed at CD33, patients also received a maintenance treatment after transplantation.

The drug, gemtuzumab ozogamicin, is not a CD33-targeted CAR-T therapy. Instead, it is an engineered antibody that recognizes CD33 and delivers an anti-cancer drug directly to 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 the 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 Engrafted

All 30 patients achieved engraftment by 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 by day 16, on average.

Those recovery times were similar to what is typically seen with standard stem cell transplantation.

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 gene-edited 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 seen during treatment were broadly 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 resulted from progression of the cancer, while three were linked to transplant-related complications, including kidney failure, liver toxicity and sepsis.

DiPersio said the findings provide a foundation for future treatments that pair CD33-deleted stem cell transplantation with CD33-targeted immunotherapies. The goal is to allow doctors to attack cancer cells more aggressively without simultaneously destroying the 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 conducted.