A phase 1 feasibility trial of BE-CAR33, an "off-the-shelf" base-edited CAR33 T cell therapy for acute myeloid leukemia.
This single-center phase 1 study treated three pediatric patients with relapsed/refractory AML, plus one adult through compassionate access, with donor-derived multiplex base-edited anti-CD33 CAR T cells, demonstrating manufacturing and delivery feasibility, manageable but substantial toxicities, and minimal residual disease reductions in two patients who proceeded to allogeneic transplantation, although the primary endpoints were not met.
Open original publication →What the AI sees
This single-center phase 1 study treated three pediatric patients with relapsed/refractory AML, plus one adult through compassionate access, with donor-derived multiplex base-edited anti-CD33 CAR T cells, demonstrating manufacturing and delivery feasibility, manageable but substantial toxicities, and minimal residual disease reductions in two patients who proceeded to allogeneic transplantation, although the primary endpoints were not met.
Research significance
The reported evidence shows that BE-CAR33 cells can be administered as an off-the-shelf bridge to allogeneic transplantation and can produce measurable disease reduction in some patients; it remains an inference requiring larger controlled studies that multiplex editing, donor sourcing, and potentially multiantigen targeting will provide a safe, durable, and broadly effective AML therapy.
Source 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.