• Robert Chiesa, Christos Georgiadis, Farhatullah Syed, Hong Zhan, Annie Etuk, Soragia Athina Gkazi, Roland Preece, Giorgio Ottaviano, Toni Braybrook, Jan Chu, Agnieszka Kubat, Stuart Adams, Rebecca Thomas, Kimberly Gilmour, David O'Connor, Ajay Vora, Waseem Qasim, and Base-Edited CAR T Group.
• From Great Ormond Street Hospital for Children NHS Trust (R.C., G.O., T.B., J.C., S.A., R.T., K.G., D.O., A.V., W.Q.) and the UCL Great Ormond Street Institute of Child Health (C.G., F.S., H.Z., A.E., S.A.G., R.P., A.K., W.Q.) - both in London.
• N. Engl. J. Med. 2023 Sep 7; 389 (10): 899910899-910.

BackgroundCytidine deamination that is guided by clustered regularly interspaced short palindromic repeats (CRISPR) can mediate a highly precise conversion of one nucleotide into another - specifically, cytosine to thymine - without generating breaks in DNA. Thus, genes can be base-edited and rendered inactive without inducing translocations and other chromosomal aberrations. The use of this technique in patients with relapsed childhood T-cell leukemia is being investigated.MethodsWe used base editing to generate universal, off-the-shelf chimeric antigen receptor (CAR) T cells. Healthy volunteer donor T cells were transduced with the use of a lentivirus to express a CAR with specificity for CD7 (CAR7), a protein that is expressed in T-cell acute lymphoblastic leukemia (ALL). We then used base editing to inactivate three genes encoding CD52 and CD7 receptors and the β chain of the αβ T-cell receptor to evade lymphodepleting serotherapy, CAR7 T-cell fratricide, and graft-versus-host disease, respectively. We investigated the safety of these edited cells in three children with relapsed leukemia.ResultsThe first patient, a 13-year-old girl who had relapsed T-cell ALL after allogeneic stem-cell transplantation, had molecular remission within 28 days after infusion of a single dose of base-edited CAR7 (BE-CAR7). She then received a reduced-intensity (nonmyeloablative) allogeneic stem-cell transplant from her original donor, with successful immunologic reconstitution and ongoing leukemic remission. BE-CAR7 cells from the same bank showed potent activity in two other patients, and although fatal fungal complications developed in one patient, the other patient underwent allogeneic stem-cell transplantation while in remission. Serious adverse events included cytokine release syndrome, multilineage cytopenia, and opportunistic infections.ConclusionsThe interim results of this phase 1 study support further investigation of base-edited T cells for patients with relapsed leukemia and indicate the anticipated risks of immunotherapy-related complications. (Funded by the Medical Research Council and others; ISRCTN number, ISRCTN15323014.).Copyright © 2023 Massachusetts Medical Society.

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