Universal Base-Edited CAR7 T Cells for T-Cell Acute Lymphoblastic Leukemia
Robert Chiesa, Christos Georgiadis, Hebatalla Rashed, Roland Preece, Prudence Hardefeldt, Jan Chu, Jemma Selvage, Avijeet Kumar Mishra, Batoul Ahmed, Stuart Adams, Rebecca Thomas, Kimberly Gilmour, Annie Etuk, Deborah Yallop, David O’Connor, Waseem Qasim
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.).