Long term remission and survival in patients with relapsed or refractory non-Hodgkin lymphoma after treatment of brl-201, a CRISPR-based non-viral PD-1 locus specifically integrated anti-CD19 CAR-T cells: 4-year follow-up of a first-in-human phase I study

作者：Yongxian Hu, Qian Tan, Jiqin Zhang, Mingming Zhang, Wenjun Wu, Guoqing Wei, Binghe Tan, Jiazhen Cui, Yuxuan Wu, Dali Li, Bing Du, Mingyao Liu, He Huang · 发表于：Blood · 年份：2025 · DOI：10.1182/blood-2025-5930 · 被引用次数：1 · 研究领域：CAR-T cell therapy research、CRISPR and Genetic Engineering、Protein Degradation and Inhibitors

Abstract BACKGROUND: Currently approved CAR-T products were all derived from viral vector transfection, which increases a potential tumorigenesis risk for patients' long-term survival, and manufacturing costs as well. We developed a novel, non-viral, CRISPR/Cas9-mediated PD-1 locus specifically integrated anti-CD19 CAR-T cells (BRL-201) to address these limitations. In the first-in-human phase I study for the treatment of relapsed/refractory (r/r) non-Hodgkin's lymphoma (NHL) patients (NCT04213469), our preliminary results showed a promising efficacy with a pretty good safety profile. Here, we update the patients with long term sustained remission after at least 4-year follow up. A phase I/II of BRL-201 (NCT05741359) is ongoing in multi-center with a large sample size to further evaluate of BRL-201 antitumor activity in China. AIM： The study aims to evaluate the tolerability and safety of escalated doses of BRL-201 in patients with r/r B-cell NHL. METHODS: The eligible participants underwent leukapheresis followed by lymphodepletion regimen with cyclophosphamide (500mg/m², D-3 to -2) and fludarabine (30mg/m², D-4 to -2) before BRL-201 infusion. Three dose levels (2.0, 4.0, and 6.0 × 10⁶ CAR-positive cells/kg) were designed with a single infusion using a 3+3 dose-escalation schema. Additional non-standard doses (0.56-0.8 × 10⁶ CAR-positive cells/kg) were also administered to three subjects. The final recommended optimal dose was 2.0 × 10⁶ CAR-positive cells/kg in the extended ...