Base-Edited CAR-T in Relapsed Childhood T-Cell ALL

Results from a Phase 1 study were recently published in The New England Journal of Medicine that provided encouraging interim results in patients undergoing treatment for relapsed T-cell acute lymphoblastic leukemia (ALL).1 This novel immunotherapy approach uses base-edited chimeric antigen receptor (CAR) T cells that recognize CD7 antigens (CAR7) and provides some early insight into remarkable responses seen in some patients with advanced disease.

The majority of children with T-cell ALL can be treated with standardized chemotherapy, but those with induction failure or with elevated minimal residual disease (MRD) after consolidation generally proceed to allogeneic stem-cell transplantation (ASCT). Patients who relapse after ASCT have a dismal prognosis. The treatment of T-cell cancers has been challenging to date given that targeting of T-cell antigens may trigger CAR T-cell fratricide (i.e., CAR T cells target one another because each expresses the protein that it is engineered to target) and may have damaging effects on the broader T-cell population.

Base editing using CRISPR technology is used to create universal CAR T cells that express a CAR that specifically recognizes CD7 antigens. This is performed by transducing healthy volunteer donor T cells with the use of a lentivirus. The base editing inactivates genes encoding CD52 and CD7 receptors and the β chain of the αβ T-cell receptor. This, theoretically, allows the T cells to evade lymphodepleting serotherapy, CAR7 T-cell fratricide, and graft-versus-host disease.

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. The study was initiated in April 2022 and included 10 participants between the ages of 6 months and 16 years with relapsed or refractory CD7+ T-cell cancer. The published results were from the first 3 patients.

Data includes a 13-year-old girl with relapsed T-ALL following ASCT. The patient received a single dose of base-edited CD7-targeted CAR (BE-CAR7) T-cells followed by a reduced-intensity ASCT. The patient had molecular remission within 28 days after infusion, successful immunologic reconstitution, and ongoing leukemia remission. On day 2 after infusion, grade 2 cytokine release syndrome (CRS) was observed requiring the administration of fluid boluses and which resolved on day 8. A grade 1 immune effector cell–associated neurotoxicity syndrome resolved spontaneously by day 12 and was treated with a short course of glucocorticoid therapy.

Data from 2 other patients were also reported who received BE-CAR7 cell infusion. One patient, a 13-year-old boy, had T-ALL of 3 years duration which relapsed (manifested as persistent cytopenia with more than 80% CD7-expressing blasts in bone marrow) while receiving maintenance treatment. After BE-CAR7 infusion, partial remission was observed with evidence of MRD. The patient had CRS that resolved on day 9 but he died after progressive lung complications from overlapping Aspergillus niger infection at day 33 after infusion.

The 3rd patient was a 15-year-old boy who underwent a first ASCT to treat a mixed phenotype acute leukemia. After minimal residual disease was detected in bone marrow, he underwent 2 donor lymphocyte infusions. After disease relapse, the disease transitioned to CD7+ T-cell ALL. After lymphodepletion, BE-CAR7 T cells were infused. Grade 2 CRS symptoms were observed but resolved after the administration of anti-IL6 treatment. BE-CAR7 T-cells were detected in his blood and bone marrow, and at day 28 an assessment revealed complete morphologic and molecular remission.

The authors’ research suggests that base editing may be promising as a therapeutic approach for ALL and that the study results are consistent with previous studies showing the antileukemic effects of allogeneic CAR T cells leading to remission of T-cell ALL. Nonetheless, the treatment is not without significant risk, including the potential for immunosuppression, CRS and cytopenia. Similar studies in the United States are underway including 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.

¹Chiesa R MD, Georgiadis C PhD, Syed F PhD, et al. Base-edited CAR7 T cells for relapsed T-cell acute lymphoblastic leukemia. N Engl J Med. 2023. DOI: 10.1056/NEJMoa2300709.