CD33 Gene Editing Enters Clinical Testing in AML | A New CRISPR-Enabled Targeted Therapy Strategy
Acute myeloid leukemia (AML) is a hematologic malignancy arising from myeloid hematopoietic cells.
In recent years, advances in targeted and immune therapies have accelerated the development of treatment strategies directed against leukemia-associated antigens. CD33 (cluster of differentiation 33), which is highly expressed on the surface of AML cells in many patients, has long been regarded as a therapeutically important target.
However, CD33 is expressed not only on AML cells but also on subsets of normal myeloid cells and myeloid progenitors. Conventional CD33-directed therapies may therefore affect normal hematopoiesis while recognizing leukemic cells, resulting in on-target, off-tumor toxicity and continuing safety challenges.
In May 2026, a phase 1/2a study published in Nature Medicine presented an innovative approach. The investigators used CRISPR-Cas9 to delete CD33 in donor hematopoietic stem and progenitor cells, creating normal hematopoietic cells that lack CD33 expression after transplantation. The strategy is intended to preserve the potential of CD33-directed therapy while reducing damage to normal hematopoiesis, providing early clinical evidence for a new precision-treatment approach in AML.
01
The Challenge of CD33-Directed Therapy
CD33 is a myeloid cell-surface receptor expressed at high levels on leukemic cells in most patients with AML, making it an important target for AML immunotherapy.
Current CD33-directed strategies include antibody-drug conjugates (ADCs), bispecific antibodies, and CAR-T-cell therapies. Gemtuzumab ozogamicin (GO), a CD33-directed ADC, has been approved for selected AML indications.
CD33 is not specific to AML cells. Because subsets of normal myeloid cells and myeloid progenitors also express CD33, CD33-directed therapies may damage normal myeloid cells while eliminating leukemic cells, increasing the risk of treatment-related cytopenias and infections.
Accordingly, a central goal in this field is to eliminate CD33-positive leukemic cells as precisely as possible while preserving normal hematopoiesis.
02
CRISPR Enables a New Therapeutic Strategy
In this study, the investigators developed a gene-edited, CD33-deleted hematopoietic stem and progenitor cell strategy.
The core approach uses CRISPR-Cas9 to delete CD33 in donor CD34+ hematopoietic stem and progenitor cells so that the normal hematopoietic cells generated after transplantation no longer express, or express substantially less, CD33.
Patients subsequently received maintenance treatment with the CD33-directed drug gemtuzumab ozogamicin (GO).
Because the edited normal hematopoietic cells lack CD33 expression, they may be less susceptible to GO-mediated cytotoxicity, while residual CD33-positive leukemic cells can still be recognized and eliminated by GO.
This strategy establishes a treatment model in which normal cells are first modified by gene editing and tumor cells are then targeted with a precision therapy. It also represents an important expansion of CRISPR from disease-gene correction to functional engineering of therapeutic cells.
03
CD33 Gene Editing Enters Clinical Validation
This phase 1/2a trial enrolled 30 adults with AML or myelodysplastic syndrome (MDS) at high risk of relapse.
The study reported the following findings:
· All patients who received transplantation with CD33-deleted hematopoietic stem cells achieved neutrophil engraftment within 28 days;
· The median time to engraftment was 10 days;
· The median level of CD33 editing in the manufactured cell product was approximately 90%;
· No prolonged high-grade cytopenias were observed during GO dose escalation;
· CD33-deleted donor-derived hematopoietic cells maintained multilineage differentiation over time.
These findings should be interpreted in context. This was an early-stage, nonrandomized study focused primarily on safety, and the trial was terminated early for financial reasons. Cytopenias and infections were among the most common adverse events, and three transplant-related deaths were reported. The results therefore support feasibility and preliminary safety rather than definitive efficacy; long-term outcomes and the risk-benefit profile in broader patient populations require further study.
The findings indicate that CRISPR-edited hematopoietic stem and progenitor cells can achieve rapid, stable engraftment while maintaining multilineage hematopoietic reconstitution, providing evidence of feasibility and preliminary safety for reducing toxicity to normal hematopoiesis during CD33-directed therapy.
04
Summary and Outlook
The significance of this study extends beyond CD33 and illustrates a new application model for gene editing in cell therapy.
While conventional cell therapies often focus on producing immune cells with therapeutic activity, this study demonstrates another approach: precisely modifying a target antigen on normal transplanted cells to create a wider safety window for subsequent targeted therapy.
As the clinical application of CRISPR gene editing in precision AML treatment enters early validation, stable and reliable CD33-edited cell models can provide important tools for CD33-targeted drug screening, CAR-T potency evaluation, and related mechanistic studies.
EDITGENE has developed a range of in-stock CD33 gene-edited cell models. Selected products are listed below:
| Catalog | Product | Gene | Order Now |
|---|
| EDJ-KQ17685 | CD33 Knockout HEK293 Cell Line | CD33 | Order Now |
| EDJ-KQ18435 | CD33 Knockout HCT116 Cell Line | CD33 | Order Now |
| EDJ-KQ61303 | CD33 Knockout A549 Cell Line | CD33 | Order Now |
| EDJ-KQ52833 | CD33 Knockout HeLa Cell Line | CD33 | Order Now |
Beyond the in-stock products listed above, EDITGENE provides custom Knockout, Knock-in, and Point-mutation cell model development tailored to specific research needs. Our end-to-end workflow covers feasibility assessment, sgRNA design and editing, monoclonal screening, and genotype validation, supporting gene-function studies, target-mechanism research, and in vitro evaluation of candidate therapies.
References
[1] DiPersio J F, Koehne G, Shah N N, et al. CRISPR−Cas9 CD33-deleted allogeneic hematopoietic cell transplantation with gemtuzumab ozogamicin maintenance in AML: a phase 1/2 trial. Nature Medicine, 2026, 32:1763-1772.
[2] Borot F, Humbert O, Ehmsen J T, et al. Multiplex base editing to protect from CD33 directed drugs for immune and gene therapy. Nature Communications, 2025, 16:4899.
[3] Laszlo G S, Estey E H, Walter R B. The past and future of CD33 as a target in acute myeloid leukemia. Blood Reviews, 2014, 28(4):143-153.
[4] Castaigne S, Pautas C, Terré C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. The Lancet, 2012, 379(9825):1508-1516.
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