Work

Infusional N-Acetylcysteine Enhances CAR T Cell Persistence in Patients with Aggressive B-Cell Lymphomas

Year: 2025

Type: article

Abstract: Background CD19-targeted CAR T cell therapy is highly effective in patients with aggressive B-cell lymphomas, but sustained remissions in patients after 2 lines of therapy are achieved in only 25-40%. Both limited cell persistence and expression of inhibitory receptors associated with an ‘exhausted’ phenotype might account for treatment failure. Persistent activation of tumor-infiltrating T-cells has been shown to result in accumulation of reactive oxygen species (ROS), mitochondrial depolarization, loss of proliferative capacity, and T-cell exhaustion. Pre-clinical work showed N-acetylcysteine (NAC) supplementation was sufficient to restore T-cell proliferative capacity and attenuate exhaustion during chronic antigen stimulation . This clinical trial was designed to test whether the administration of NAC to patients can improve the persistence of CD19+ CAR T therapy. Method This phase I prospective trial used 3+3 design to study of 3 dose levels (DL; 1.5g/day, 3g/day, and 6g/day) with the primary objective to determine the safety, tolerability , and maximum tolerated dose (MTD) of N-acetylcysteine (NAC) in patients with relapsed/refractory lymphoma undergoing commercial axicabtagene ciloleucel (Axi-cel) CAR T cells (NCT05081479). NAC infusion began on Day-1, was infused continuously for up to 14 days or until time of discharge and was interrupted if patients had any grade cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) and potentially resumed if resolved. CAR-T persistence was compared with a convenience sample of patients receiving axi-cel as part of standard of care therapy. Results Between January 2022 and October 2023, 9 patients completed 3 dose levels (median age 56 (20-78); 67% male; 89% white; 67% ECOG 0; diffuse large B-cell lymphoma (n=7), primary mediastinal B cell lymphoma (n=1), high grade B cell lymphoma (n=1); median 2 prior lines of therapy (1-4)). Eight patients received cyclophosphamide/fludarabine (Flu/Cy) for lymphodepletion, and all received 2 × 10^8 CAR T cells . All patients had CRS requiring NAC to be held at a median of Day 4 (Day 2-5, Figure 1 and 2). Median progression free survival was 10 months (3.2 – 22.4mo) with 3 deaths due to disease progression . Preliminary correlative analysis indicates that NAC substantially increased CAR-T persistence at 1 week (29.7% vs. 4.6% of all viable cells, p = 0.026) in evaluated patients who received Flu/Cy, while PD1 expression was reduced (Figure 3). Conclusion NAC can be safely co-administered with Axi-cel without substantial toxicity. Preliminary analysis suggests increased CAR T persistence in vivo with NAC treatment compared to historical controls. Peripheral blood soluble cytokine and single-cell transcriptomic analysis is ongoing.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2025.01.363