"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 serves as the director of 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."
The potential of this "deletion-shielding" approach was highlighted in a remarkable single-case report involving a patient with high-risk AML. After receiving a CD33-deleted stem cell transplant, the patient eventually faced a recurrence of the cancer. Because the patient’s healthy blood system was now "CD33-negative," doctors were able to administer CD33-targeted CAR-T cells derived from the original stem cell donor.
The results were profound. The patient, who suffered from one of the most aggressive and traditionally untreatable forms of AML, entered a state of complete remission. More than a year after the CAR-T intervention, the patient remained cancer-free. Crucially, the patient’s normal blood cell production returned to healthy levels, and all those new cells lacked the CD33 protein. This confirmed that the genetically engineered donor cells had successfully and permanently established themselves in the bone marrow, providing a durable and "invisible" foundation for the patient’s blood system. This specific case study was published in the October 2025 issue of JCO Precision Oncology.
Shielding Healthy Blood Cells
CD33 is considered an ideal target for this gene-editing strategy for several reasons. First, the protein is found almost exclusively on blood-forming cells and is not present on other vital tissues, such as the heart, lungs, or liver. Second, and perhaps most importantly, CD33 appears to be non-essential for the normal functioning of blood stem cells. Research has shown that individuals born with a natural genetic deficiency of CD33 do not suffer from any apparent health problems or immune deficiencies.
By using CRISPR gene-editing technology to remove CD33 from donor stem cells, researchers essentially create a biological "blind spot" for therapies. Once the edited cells are transplanted and begin to proliferate, any cell in the patient’s body still carrying the CD33 protein is, by definition, a malignant cell. This allows a CAR-T therapy or a targeted antibody to act like a heat-seeking missile that can only see the cancer, leaving the healthy, donor-derived blood system untouched.
The Phase 1/2 multicenter trial focused on 30 adults with AML or MDS who were at high risk of relapse—a group for whom standard transplant protocols often fail. The gene-edited stem cell product used in the trial is known as tremtelectogene empogeditemcel, or "trem-cel." Developed by the biotechnology company Vor Biopharma, which also funded the study, trem-cel represents one of the first applications of CRISPR-edited donor tissue to be tested at this scale.
Testing a CD33-Targeted Cancer Treatment
To prove that these edited stem cells could truly withstand a CD33-directed attack, the trial included a "stress test" in the form of post-transplant maintenance therapy. Patients were given gemtuzumab ozogamicin, an FDA-approved drug for CD33-positive AML.
Unlike CAR-T therapy, gemtuzumab ozogamicin is an antibody-drug conjugate. It consists of an engineered antibody that seeks out CD33 and delivers a potent anti-cancer toxin directly into the cell. While the drug is effective at preventing relapse, its clinical utility has historically been restricted by its toxicity. It frequently causes severe liver damage and "myelosuppression"—a dangerous drop in white blood cells, red blood cells, and platelets—because it attacks the healthy blood-forming cells that also carry CD33.
In this trial, however, the researchers hypothesized that the CD33-deleted "trem-cel" would be immune to the drug’s destructive side effects. If the theory held, patients could receive the maintenance therapy safely, keeping the cancer at bay while their blood counts remained stable.
