Lineage Plasticity-Mediated Resistance to CD7-Directed CAR-T Therapy in Relapsed/Refractory T-ALL/LBL.

Abstract

CD7-directed chimeric antigen receptor (CAR) T-cell therapy has shown promising efficacy in relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma (T-ALL/LBL). However, relapse remains a major obstacle. We generated a recyclable CD7 CAR-T cells (CD7 CAR^Recyclable) and conducted a phase I clinical trial to evaluate its safety and response in patients with R/R T-ALL/LBL (NCT05290155). Fourteen patients received CAR-T cells and were evaluable for safety and response. Immunophenotypic and molecular profiling were performed longitudinally to characterize relapse patterns. Robust CAR-T expansion was observed in 13 of 14 patients (92.9%). Peak CAR-T concentration (Cmax) reached 62,389.69 copies/μg DNA (range: 3175.94 to 326,482.67) at median 12 days postinfusion (range: 10 to 21). All patients experienced hematologic toxicities, and cytokine release syndrome occurred in 71.4% of patients, predominantly grade 1 to 2. While ICANS developed in 2 patients (14.3%, grade 2 and 3) at day 8 and 28, respectively. Three out of 4 patients achieved measurable residual disease (MRD)-negative complete remission in bone marrow, while the objective response rate for extramedullary disease was 78.6%. With a median follow-up of 8.5 months, the estimated 6-month overall survival (OS) and progression-free survival (PFS) were 62.3% and 44.6%, respectively. Notably, lineage switch relapse occurred in 2 patients with ETP-immunophenotype following CAR-T therapy. These findings suggest that lineage plasticity might represent an under-recognized mechanism of resistance to CD7-directed CAR-T therapy in T-ALL/LBL, particularly in ETP-ALL/LBL, warranting further exploring.