A collaborative study by University College London and Hannover Medical School reveals the promise of base-edited donor chimeric antigen receptor (CAR) T-cell therapies in treating acute myeloid leukaemia (AML), potentially providing renewed hope for patients with relapsed or refractory disease.
Children and adults with relapsed or refractory AML continue to experience poor long-term survival despite intensive treatment regimens. CAR T-cell therapy offers a promising alternative.
However, targeting a single antigen has proved less effective in AML than in B- or T-cell malignancies, mainly due to the high degree of inter- and intra-patient phenotypic heterogeneity.
Targeting multiple antigens with CAR T-cells
This study investigated base-edited CAR (BE-CAR) T-cells engineered to target the CD33 (BE-CAR33), CLL-1 (BE-CARCLL-1) and CD7 (BE-CAR7) antigens in AML.
These ‘universal’ donor cells were created using cytidine base editing to delete TCRαβ, preventing graft-versus-host disease; CD7 to avoid cell fratricide; and CD52, conferring resistance to alemtuzumab.
The research utilised AML cell lines, primary patient samples and patient-derived xenograft (PDX) models derived from a patient with a t(3;3) translocation. In vivo experiments were performed in immunodeficient NSG mice grafted with AML cells and treated with BE-CAR T cells.
Efficacy in heterogeneous AML
In vivo, monotherapy with BE-CAR33 or BE-CARCLL-1 effectively targeted AML with uniform antigen expression, while combined therapy was required to eradicate heterogeneous disease. Co-infusion with BE-CAR7 cells was feasible following CD7 editing of BE-CAR33/CLL-1 cells.
In a CD33-high/CD7-low PDX model, BE-CAR33 monotherapy improved survival, underscoring its efficacy against specific antigen profiles.
The results demonstrated that BE-CAR T cells exhibited potent, antigen-specific cytotoxicity. Combined BE-CAR33 and BE-CARCLL-1 therapy successfully eliminated heterogeneous AML, while CD7 editing enabled compatibility with BE-CAR7 cells without compromising anti-leukaemic activity.
The study’s limitations included reliance on murine models and the need for validation in human trials. The researchers also noted the challenge of antigen overlap with healthy tissues and emphasised the importance of time-limited CAR T-cell therapy.
Future work will focus on a phase 1 evaluation of BE-CAR33 in children aged six months to 16 years (NCT05942599) and the development of combinatorial strategies tailored to patient-specific antigen expression, the researchers added.
It is hoped that this approach may help to address disease heterogeneity, support pre-transplant conditioning and offer renewed hope for relapsed or refractory patients preparing for allogeneic stem cell transplantation.
Reference
Kadirkamanathan R et al. Base edited “universal” donor CAR T-cell strategies for acute myeloid leukaemia. Leukemia 2025; 1 Oct: doi: 10.1038/s41375-025-02720-5.
