Abstract
Background Relapse following CAR-T therapy bridged to allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents a therapeutic challenge with limited salvage options. Secondary autologous CAR-T therapy demonstrates poor efficacy due to anti-CAR immune responses and T-cell exhaustion. Donor-derived CAR-T (ddCAR-T) cells offer theoretical advantages by bypassing preexisting immunity while providing both CAR-mediated targeting and graft-versus-leukemia effects. This represents the first systematic evaluation of donor-derived secondary CAR-T (ddCAR-T2) therapy in this unique clinical scenario.
Methods We conducted a retrospective analysis of patients with hematological malignancies who received ddCAR-T2 therapy between November 2021 and January 2025 following relapse after initial CAR-T treatment bridged to allo-HSCT. Patients received fludarabine and cyclophosphamide lymphodepletion followed by ddCAR-T2 cells targeting CD19 (n=5), CD7 (n=1), or BCMA (n=1) using 4-1BB costimulatory domains. The primary endpoint was overall response rate. Secondary endpoints included overall survival (OS), event-free survival (EFS), and safety assessments per CTCAE v5.0.
Results Seven patients were enrolled with a median age of 34 (range 18-67) years. The cohort included 5 B-cell acute lymphoblastic leukemia(ALL), 1 T-cell ALL, and 1 primary plasma cell leukemia patients. Median infusion dose was 3.5 (range 2.0-5.0) × 10⁶/kg CAR-T cells.Among 7 patients, 6 (85.7%) achieved minimal residual disease-negative complete remission within 1 month post-infusion. All 3 patients with isolated extramedullary disease demonstrated complete metabolic remission on PET-CT imaging. CAR-T2 cells demonstrated superior expansion kinetics compared to initial CAR-T therapy, with significantly higher peak expansion levels and shorter time to peak (median 11 vs 14 days, P=0.02). During ddCAR-T2 therapy, cytokine release syndrome occurred in all patients but was limited to grade 1-2 severity (grade 1: 42.9%, grade 2: 57.1%). No grade ≥3 CRS or immune effector cell-associated neurotoxicity syndrome was observed. One patient (14.3%) developed grade 3 acute GVHD and died from refractory aGVHD complicated by infection on day 70. At median follow-up of 540 days (range 70-1290), 6 patients (85.7%) maintained durable event-free survival. Median OS and EFS were not reached; 2-year OS and EFS rates were both 85.7% (95% CI: 33.4-97.9%).
Conclusions For patients experiencing relapse after initial CAR-T bridged to allo-HSCT, ddCAR-T2 therapy demonstrates remarkable efficacy (85.7% MRD-negative CR) and acceptable safety. Superior cellular kinetics and broad target applicability (CD19, CD7, BCMA) establish this approach as a promising salvage strategy for this challenging population.
DisclosuresNo relevant conflicts of interest to declare.
