Clinical trial combines CRISPR gene editing with stem cell transplants to treat aggressive blood cancers

For patients facing aggressive blood cancers like acute myeloid leukemia, survival often depends on a stem cell transplant. Even then, the fear of relapse lingers. Many patients watch their cancer return after enduring months of exhausting treatment, harsh chemotherapy and risky transplantation procedures.

Now, researchers at Washington University School of Medicine in St. Louis have reported encouraging results from a clinical trial that may help change that future. Their work combines CRISPR gene editing with stem cell transplantation to protect healthy donor cells while allowing targeted cancer therapies to attack leukemia more effectively.

The study involved researchers at Siteman Cancer Center and 14 additional sites across the United States and Canada. Scientists believe the findings could eventually help solve one of the biggest challenges in treating certain blood cancers.

Acute myeloid leukemia, known as AML, and myelodysplastic syndrome, called MDS, are aggressive cancers that begin in blood-forming cells inside the bone marrow. Standard treatments often fail to eliminate every cancer cell. Even after stem cell transplantation, relapse remains common.

Doctors have long hoped that CAR-T cell therapy could improve outcomes. CAR-T therapy works by engineering immune cells to recognize and destroy cancer. It has transformed treatment for some blood cancers, but AML and MDS have remained stubbornly difficult.

The problem centers on a protein called CD33. Leukemia cells carry CD33 on their surface, making it an appealing target for therapy. Unfortunately, healthy blood-forming cells also carry the same protein.

That overlap creates serious risks. CAR-T cells or other CD33-targeted therapies may attack healthy donor stem cells alongside cancer cells. This can destroy blood production and trigger dangerous inflammation.

“As such, the anti-cancer therapy carries a high risk of toxicity because it also destroys healthy blood stem cells,” explained study author John F. DiPersio, MD, PhD, of Washington University School of Medicine.

Researchers wanted to find a way around that problem. Their answer involved editing donor stem cells before transplantation.

The research team used CRISPR gene editing technology to remove CD33 from donor stem cells before transplant. The edited product is called tremtelectogene empogeditemcel, or trem-cel.

Scientists believed CD33 was a good candidate for deletion because healthy people can naturally lack the protein without obvious health problems. CD33 also mainly appears on blood-forming cells rather than other organs.

The idea was simple but powerful. If healthy donor cells no longer carried CD33, doctors could later use therapies targeting CD33 without damaging the rebuilt blood system.

“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,” DiPersio said.

The work builds on earlier research led by Miriam Y. Kim, MD, now an assistant professor of medicine at Washington University. Kim began studying this concept while working as a postdoctoral researcher at the University of Pennsylvania before continuing the work in DiPersio’s lab.

The phase 1 and 2 clinical trial enrolled 30 adults with high-risk AML or MDS. Twenty-nine had AML and one had MDS. More than half carried multiple high-risk features, including adverse genetics or measurable residual disease before transplant.

Patients first received intensive conditioning treatment to destroy diseased bone marrow. They then received donor stem cells that had undergone CRISPR editing to remove CD33.

Researchers measured how well the edited cells rebuilt the blood system. They also monitored whether patients could safely receive a maintenance therapy called gemtuzumab ozogamicin, or GO, after transplant.

GO is an antibody-drug conjugate already approved for some AML patients. It targets CD33 and delivers a toxic drug directly into leukemia cells. However, its use after transplantation has been limited because it can severely damage healthy blood cells.

Scientists hoped the edited donor cells would resist GO therapy while leukemia cells remained vulnerable.

The results offered encouraging signs. All 30 patients achieved neutrophil engraftment within 28 days. This means the donor stem cells successfully settled into the bone marrow and began producing blood cells.

The median time to neutrophil recovery was only 10 days. Platelet recovery occurred in nearly all patients by a median of 16 days. Those recovery times resembled standard stem cell transplants, suggesting that removing CD33 did not impair the donor cells.

Nineteen patients later received at least one cycle of GO maintenance therapy. Some completed several cycles. Researchers found that blood counts remained stable during treatment.

Importantly, patients avoided the severe and prolonged blood cell suppression commonly associated with GO after standard transplantation.

“No prolonged high-grade cytopenias were observed,” the study reported.

Researchers also confirmed that edited CD33-negative cells persisted across several immune cell types, including T cells, B cells and natural killer cells. Blood-forming function appeared normal.

The treatment still carried significant risks. Serious side effects included anemia, low platelet counts, infections and graft-versus-host disease, a condition where donor immune cells attack healthy tissues.

Twenty-six patients experienced infections during the study. Some developed pneumonia, COVID-19 or viral infections. Seven patients died during the trial. Four deaths resulted from cancer progression. Three stem cell transplant-related deaths involved kidney failure, liver toxicity or sepsis.

Despite those complications, researchers said the safety profile resembled standard transplantation for such high-risk patients.

The median overall survival reached 14.1 months. About 40% of patients remained relapse-free at roughly two years, although follow-up remains limited.

Researchers also described a separate patient case that highlights the promise of this strategy. The patient had one of the most aggressive forms of AML and relapsed after receiving a CD33-deleted transplant.

Doctors later treated the patient with CD33-targeted CAR-T cells derived from the same donor who provided the transplant cells. The patient entered complete remission and remained cancer-free more than one year later.

Researchers also observed healthy blood production from donor cells lacking CD33, showing that the engineered cells successfully rebuilt the marrow.

This case provided an important proof of concept. It suggested that pairing gene-edited transplantation with targeted immunotherapy could create a more focused attack against leukemia while sparing healthy blood cells.

Scientists say the findings could reshape how doctors think about stem cell transplantation and immunotherapy for myeloid cancers.

Traditionally, shared proteins like CD33 created major treatment barriers because therapies could not distinguish between healthy and cancerous blood cells. Gene editing may change that equation.

Instead of avoiding CD33, researchers removed it from healthy donor cells entirely. That transformed CD33 into a cleaner target for future therapies.

“This study lay the groundwork for developing paired CD33-deleted stem cell transplant and CD33-targeted immunotherapy interventions,” DiPersio said.

Researchers caution that larger studies and longer follow-up are still needed. The trial involved only 30 patients and ended early because of financial limitations. Still, the results offer hope in a field where relapse remains devastatingly common.

For patients with AML and MDS, that hope carries enormous emotional weight. Many endure repeated rounds of chemotherapy, long hospital stays and uncertainty about whether remission will last. The possibility of safer, more targeted post-transplant therapies could eventually give doctors stronger tools to keep these cancers from returning.

This research could open the door to a new generation of cancer treatments that combine gene-edited stem cell transplantation with targeted immunotherapies. By protecting healthy donor blood cells from therapies aimed at CD33, doctors may eventually use CAR-T cells and other precision treatments more safely in AML and MDS.

The approach may also improve long-term remission rates for patients at high risk of relapse after transplantation. If future studies confirm these findings, hospitals could adopt gene-edited donor cells as part of standard treatment for aggressive blood cancers.

Beyond AML and MDS, the work demonstrates how CRISPR editing may solve problems where cancer targets also appear on healthy tissue. Researchers could potentially adapt similar strategies for other diseases in the future.

Research findings are available online in the journal Nature Medicine.

The original story "Clinical trial combines CRISPR gene editing with stem cell transplants to treat aggressive blood cancers" is published in The Brighter Side of News.

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