Base-Edited CD7-CAR T Cells Show Early Efficacy in T-ALL


New data from 3 patients were published in the New England Journal of Medicine.

Interim data from a phase 1 study (NCT05397184) of base-edited chimeric antigen receptor (CAR) T-cells show a potential clinical benefit for patients with relapsed T-cell acute lymphoblastic leukemia (T-ALL).

“Cytidine 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,” first author Robert Chiesa, MD, consultant, pediatric bone marrow transplantation & CAR-T cell therapy, Great Ormond Street Hospital, London, United Kingdom, and colleagues wrote.

Data reported include a 13-year-old girl with relapsed T-ALL after allogeneic stem cell transplant. The patient received a single dose of base-edited CD7-targeted CAR (BE-CAR7) T-cells and then a reduced-intensity, nonmyeloablative allogeneic stem cell transplant from her original donor. Chiesa and colleagues found that the patient had molecular remission within 28 days after infusion, successful immunologic reconstitution, and ongoing leukemia remission. The patient had a fever which developed on day 2, followed by hypotension that led to the administration of fluid boluses without additional intervention for grade 2 cytokine release syndrome (CRS), which resolved on day 8. She also had grade 1 immune effector cell–associated neurotoxicity syndrome that resolved spontaneously by day 12 and was treated with a short course of glucocorticoid therapy for suspected grade 2 graft-versus-host-disease (GvHD).

The authors also reported data from 2 other patients, both of which experienced potent activity with BE-CAR7 cell infusion. One patient, a 13-year-old boy, had T-ALL which relapsed while receiving maintenance treatment. After BE-CAR7 infusion, partial remission was observed with evidence minimal residual disease. The patient had CRS that resolved on day 9 but died after progressive lung complications from overlapping A. niger infection at day 33 after infusion.

READ MORE: Multiplex-Base Edited CAR T Therapy Cleared for Trial in T-ALL After Hold

The third patient, a 15-year-old boy, developed T-ALL after bone marrow relapse after 2 allogeneic stem cell transplants for mixed-phenotype acute leukemia. The patient had transient grade 2 CRS which resolved after 2 doses of tocilizumab, no neurotoxicity, continuing lymphopenia and viral reactivations. At day 28 after infusion, investigators found the patient had complete morphologic and molecular remission, enabling progression to a consolidative matched, unrelated donor allogeneic stem cell transplantation. Altogether, BE-CAR7's safety profile so far includes serious adverse events including opportunistic infections, CRS, and multilineage cytopenia.

“We report a proof-of-concept study that supports base editing as a therapeutic approach. Our data are consistent with the antileukemic effects of allogeneic CAR T cells, effects that are sufficient for securing remission and deep clearance of T-ALL. However, the strategy is not without risk: the immunosuppressive and cytopenic effects of the trial protocol are substantial, and immune-cell manipulation carries risks. In this study, subsequent allogeneic transplantation ensured donor-derived immune reconstitution and also limited the persistence of engineered cells.Additional safety measures could include the incorporation of a drug-inducible safety switch (or elimination system) to enable the controlled removal of infused cells once the useful therapeutic effects are derived or in the event of serious toxic effects,” Chiesa and colleagues wrote.

The investigators developed BE-CAR7 by transducing allogeneic CAR cells with a lentivirus vector to target CD7. To evade lymphodepleting serotherapy, CAR7 T-cell fratricide, and , they used base editing to inactivate 3 genes encoding CD52 and CD7 receptors and the β chain of the αβ T-cell receptor. The study was conducted by Great Ormond Street Hospital for Children NHS Trust and the University College London Great Ormond Street Institute of Child Health.

“This phase 1 study aims to recruit 10 children in the United Kingdom for an initial cohort, which includes the patients described here. Similar studies in the United States are in preparation, as well as a related approach using anti-CD33 CAR T cells for deep conditioning ahead of allogeneic stem-cell transplantation for relapsed acute myeloid leukemia in Europe,” Chiesa and colleagues concluded.

Chiesa R, Georgiadis C, Syed F, et al. Base-edited CAR7 T cells for relapsed T-cell acute lymphoblastic leukemia. Published online June 13, 2023. N. Eng J Med. doi: 10.1056/nejmoa2300709
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