Base-Edited Universal CAR-T Cells Induce Complete Remission in Relapsed T-Cell ALL
In a phase 1 trial, 11 patients with relapsed or refractory T-cell ALL received universal base-edited anti-CD7 CAR-T cells with triple gene knockouts (TCR, CD52, CD7). All patients achieved complete morphologic remission by day 28, and 9 of 11 had deep MRD-negative remission by flow cytometry or PCR, enabling stem-cell transplantation. Seven patients remained in ongoing remission at 3-36 months, demonstrating that gene-edited allogeneic CAR-T therapy with MRD-guided bridging to transplant is feasible in T-cell malignancies.
The original study
Universal Base-Edited CAR7 T Cells for T-Cell Acute Lymphoblastic Leukemia.
- Authors
- Chiesa R, Georgiadis C, Rashed H, Preece R, Hardefeldt P, Chu J, et al.
- Journal
- The New England journal of medicine
- Type
- Clinical Trial, Phase I, Journal Article
- PMID
- 41363805
Original abstract
BACKGROUND: CD7 is an attractive target for chimeric antigen receptor (CAR) T-cell therapy in relapsed or refractory T-cell acute lymphoblastic leukemia (ALL). Supportive results of first-in-human studies of base-edited anti-CD7 CAR (BE-CAR7) T cells with triple C→T deamination-mediated knockouts of TCRαβ, CD52, and CD7 have been reported previously. METHODS: In a phase 1 study, we administered BE-CAR7 T cells to children (≤16 years of age) with relapsed or refractory T-cell ALL after they had undergone lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab. Adults with compassionate-use access arrangements were also eligible. Patients who had remission by day 28 after the BE-CAR7 T-cell infusion proceeded to allogeneic hematopoietic stem-cell transplantation. The primary outcome was safety. Secondary outcomes included duration of remission, disease-free survival, and overall survival. RESULTS: BE-CAR7 T cells were administered to 9 children, as well as to 2 adults who were treated under compassionate-use access arrangements. Lymphodepletion and BE-CAR7 infusions did not lead to unacceptable adverse events, and circulating CAR7 T cells were detected in all the patients. Complications included cytokine release syndrome of grades 1 through 4, transient rashes, multilineage cytopenia, and opportunistic infections. All the patients had complete morphologic remission with incomplete count recovery at day 28. Nine patients (82%) had deep remission (according to flow cytometry or polymerase-chain-reaction assay) that allowed them to proceed to stem-cell transplantation, and 2 patients with quantifiable minimal residual disease in bone marrow received palliative care. Transplantation eliminated remaining BE-CAR7 T cells and supported donor-derived, multilineage reconstitution. Viral reactivations were frequent, and 3 patients had clinically significant virus-related complications after transplantation. Overall, 7 of the 11 patients (64%) who received the investigational therapy were in ongoing remission at 3 to 36 months after transplantation, and leukemia with loss of CD7 expression was documented in 2 patients. CONCLUSIONS: Universal BE-CAR7 T cells induced leukemic remission in patients with relapsed or refractory T-cell ALL, thus allowing successful allogeneic hematopoietic stem-cell transplantation in most of the patients. (Funded by the Medical Research Council and others; ISRCTN Registry number, ISRCTN15323014.).