Immunotherapies Gene-Edited Stem Cell Transplant Shows Promise for Aggressive Blood Cancers

Gene editing could help solve one of the biggest problems in treating aggressive blood cancers: how to attack cancer cells without destroying healthy donor cells. A new multicentre trial shows that CRISPR-modified stem cell transplants may make CD33-targeted therapies safer and more effective after transplantation.

For highly aggressive types of blood cancer, stem cell transplantation is often the only potentially curative therapy, yet even after a transplant, these cancers often return.

Now, a clinical trial, led by researchers at Washington University School of Medicine in St. Louis, shows that a stem cell transplant in which the donor cells have been genetically engineered to remove a particular protein helps prevent toxic side effects and potentially improves the effectiveness of therapies given after a transplant to help prevent cancer recurrence.

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 findings are published May 12 in the journal Nature Medicine.

According to the study’s corresponding author, John F. DiPersio, MD, PhD, the Virginia E. & Sam J. Golman Professor of Medicine at Washu Medicine, this gene-editing technology could help address a longstanding frustration in the field: CAR-T cell therapy — an immunotherapy that effectively treats some aggressive blood cancers — has not worked against all blood cancers, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

According to DiPersio, who treats patients at Siteman and is a research member there, myeloid cancers like AML and MDS are tricky to treat with CAR-T cells because the same proteins on cancer cells that the immunotherapy homes in on for destruction are also present on healthy myeloid cells, including therapeutic donor stem cells. As such, the anti-cancer therapy carries a high risk of toxicity because it also destroys healthy blood stem cells, which can trigger a dangerous inflammatory cascade. This effect also could dilute the effect of the anti-cancer therapy because so many of the CAR-T cells are attacking the wrong targets, leaving many cancer cells untouched.

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This basic concept was first described by Miriam Y. Kim, MD, now an assistant professor of medicine at Washu Medicine. She began this research as a postdoctoral researcher at the University of Pennsylvania and continued the work 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.

For this clinical trial, patients with AML and MDS received donor stem cells that had a target protein, called CD33, removed, in hopes that immunotherapy targeted against CD33 would kill the cancer and ignore the healthy cells.

“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.”

To that end, DiPersio and his collaborators have also published a single case study of a patient with high-risk AML who received a CD33-deleted stem cell transplant and later, upon relapse after the transplant, received a CD33-targeted CAR-T cell therapy, which used T cells from the same donor who provided the stem cell transplant. The patient — who had one of the most aggressive types of AML — achieved complete remission and remains cancer free over one year after receiving the CAR-T cell therapy. The patient also had normal blood cell production return with all blood cells lacking CD33, providing evidence that the genetically engineered donor cells had established themselves in the bone marrow. DiPersio is the senior author of this study, published in October 2025 in JCO Precision Oncology.

Shielding Healthy Cells

CD33 is an appealing protein to delete from donor stem cells because it is only present on blood-forming cells and not in other tissues, and because there is evidence it is not required for the proper function of blood stem cells, given that individuals born without CD33 have no apparent health problems. After a patient has successfully received this type of stem cell transplant, any remaining cells in the body with CD33 on the surface should, in theory, only be the cancer. Then, CAR-T cells or another immunotherapy designed to target CD33 would kill only the cancer cells and leave healthy donor stem cells untouched.

In this phase 1/2 multicenter clinical trial, 30 adult patients with AML or MDS at high risk of relapse received a stem cell transplant in which CD33 had been removed from the donor cells using CRISPR gene editing technology before the transplant procedure. The CD33-deleted stem cell product is called tremtelectogene empogeditemcel (trem-cel) and was made by Vor Biopharma, which funded the study.

As proof of concept, the patients also received a maintenance therapy that targets CD33, after they underwent the stem cell transplant. While not a CD33-targeted CAR-T cell, the maintenance therapy, called gemtuzumab ozogamicin, is a type of engineered antibody that targets CD33 and carries an anti-cancer drug. Gemtuzumab ozogamicin is approved by the Food and Drug Administration to treat CD33-positive AML and is in clinical trials for CD33-positive MDS. While it helps prevent relapse, the drug’s use is limited because it can cause liver toxicity and damage to blood cells, including dangerously low counts of white blood cells, red blood cells and platelets.

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All patients achieved engraftment of their transplanted stem cells by day 28, meaning the cells had gathered in the bone marrow and started working. Some patients met this goal sooner, and platelet production returned by day 16, on average. These timeframes are comparable to those of standard transplanted stem cells.

Average survival was just over 14 months. Nineteen patients received at least one cycle of the antibody maintenance therapy as part of a dose-escalation protocol, and the researchers were able to establish the recommended dose. The researchers found that patients maintained blood cell counts across all doses, suggesting that the gene-edited stem cell transplant protected patients from the dangerously low blood cell counts typically seen during this maintenance therapy following a standard stem cell transplant.

Side effects during the treatment were similar to those of standard transplants, including anemia, low platelets, fever, infections and graft-versus-host disease, in which the donor cells attack the patient’s healthy tissues. Seven patients died during the study, with four due to the cancer progressing and three due to transplant-related causes, including kidney failure, liver toxicity and sepsis.

DiPersio said the results of the study lay the groundwork for developing paired CD33-deleted stem cell transplant and CD33-targeted immunotherapy interventions that avoid destruction of healthy donor cells in the course of cancer treatment.

Original Article: CRISPR−Cas9 CD33-deleted allogeneic hematopoietic cell transplantation with gemtuzumab ozogamicin maintenance in AML: a phase 1/2 trial; Nature Medicine; DOI:10.1038/s41591-026-04362-1

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