A phase 1 feasibility trial of BE-CAR33, an "off-the-shelf" base-edited CAR33 T cell therapy for acute myeloid leukemia.

Authors

Christos Georgiadis, Robert Chiesa, Hebatalla Rashed, Bethany K Hughes, Roland Preece, Oliver Gough, Danielle Pinner, Stuart Adams, Rebecca Thomas, Annie Etuk, Avijeet Mishra, Hong Zhan, Toni Braybrook, Kimberly Gilmour, Victoria Potter, Jack Bartram, Phillip Ancliff, Martin Sauer, Waseem Qasim, Base Edited-CAR T cell group, Base-Edited CAR T Group

Published in

Science translational medicine. Volume 18. Issue 863. Pages eaei0875. Aug 19, 2026. Epub Aug 19, 2026.

Abstract

Chimeric antigen receptor (CAR) T cell therapy for acute myeloid leukemia (AML) is constrained by antigen heterogeneity and shared expression with healthy compartments, and there are often challenges in obtaining autologous T cells from heavily pretreated patients. To address these challenges, we developed universal donor-derived, base-edited, anti-CD33 CAR T cells (BE-CAR33) that used precise multiplexed cytidine deamination to simultaneously disrupt the TRAC, CD52, and CD7 loci to prevent graft-versus-host disease and evade immunotherapy effects. An open-label, nonrandomized, single-center phase 1 study (ISRCTN14430213) evaluated the safety, feasibility, and activity of BE-CAR33 cell therapy ahead of allogeneic stem cell transplantation (allo-SCT) for patients with AML. Eligible participants were aged less than 16 years with relapsed/refractory AML. Five patients were screened, and three were enrolled; one additional adult received BE-CAR33 through compassionate access. Participants received fludarabine, cyclophosphamide, and alemtuzumab followed by 1.2 to 1.8 × 10⁶ BE-CAR33 cells per kilogram. Treatment-emergent adverse events included cytokine release syndrome (grade ≤2), neurotoxicity (grade 3), cytopenias (grade 4), and transient rashes. Two patients demonstrated reduced minimal residual disease and proceeded to allo-SCT. Serial flow cytometry, chimerism quantification, and vector copy number analyses tracked BE-CAR33 T cells until elimination during transplant. Differentially expressed genes included editing signatures and switched from manufacturing-related toward postexpansion effector and exhaustion profiles. Although primary end points were not met, this first-in-human study demonstrated the feasibility of an "off-the-shelf" base-edited CAR T cell approach and informs future multiantigen strategies against AML.

PMID:
42616838
Bibliographic data and abstract were imported from PubMed on 20 Aug 2026.

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