Long term follow-up results of BRL-201 phase I study, a CRISPR-based non-viral PD-1 locus specific integrated anti-CD19 CAR-T cells in treating relapsed or refractory non-Hodgkin's lymphoma.
Authors: Zheng Biao , Hu YongXian , Zhang Jiqin , Zhang Mingming , Li Wei , Wu Wenjun , Cui Jiazhen , Wei Guoqing , Du Bing , Liu Mingyao , Huang He 
Published: July 2024

7031

Background: Conventional CAR-T cell therapy, often virus-based, poses tumorigenesis risks and incurs high costs and time. We developed a novel, non-viral, CRISPR/Cas9-mediated method for generating genome-specific integrated CAR-T cells, bypassing these limitations. Here, we update long term follow up data of trial of non-viral PD1 locus specifically integrated anti-CD19 CAR-T cells (BRL-201) in patients with relapsed/refractory (r/r) Non-Hodgkin’s lymphoma (#NCT04213469). Recently, a phase I/II of BRL-201 (#NCT05741359) is ongoing with a large-scale and multi-center design to further evaluate of BRL-201 antitumor activity in lower dose level. Methods: This phase I investigator-initiated trial evaluated BRL-201 in adult patients with r/r B-NHL. Participants underwent leukapheresis followed by lymphodepletion chemotherapy with cyclophosphamide (500mg/m², D-3 to -2) and fludarabine (30mg/m², D-4 to -2) before BRL-201 infusion. Dose escalation followed a 3+3 rule across three cohorts (2×10⁶/kg, 4×10⁶/kg, 6×10⁶/kg), with additional non-standard doses (0.56~0.8 × 10⁶/kg) administered to three subjects. Primary endpoint: incidence of dose-limiting toxicities (DLT). Secondary endpoint: proportion of patients achieving an objective response at 3 months as assessed by investigators. The phase I/II trial also employed the 3+3 escalation rule. Results: From May 3, 2020, to August 10, 2021, 25 patients with r/r B-NHL were enrolled; 21 received BRL-201, with a median age of 56 (range: 34-70) and median of 4 (range: 1-9) prior therapy lines. 17 patients were diagnosed with disease stages III or IV, and 13 patients were high-intermediate to high risk per IPI/aaIPI. Two had previous autologous HSCT, and one had primary refractory disease. As of January 10, 2024, the median follow-up was 37.0 months (95%CI: 33.82-40.18m). All 21 patients showed an objective response, with 18 (85.7%) achieving CR. 7 patients maintained CR at data cut-off. The median DOR was 18.6 months (95%CI: 4.10-33.10), with a median PFS of 19.5 months (95%CI: 5.15-33.86). The 12-month OS rate was 76.2% (95% CI: 60%-96.8%). The median OS was not reached. No severe CRS or ICANS were noted. Mild CRS (grade 1-2) occurred in 66.7%(14/21) of patients, with one requiring tocilizumab. Grade 1-2 ICANS was observed in 19.0%(4/21). No new AEs/SAEs were reported in the last follow-up. In the ongoing phase I study, 9 patients received BRL-201 with no DLTs observed within 28 days post-infusion. Conclusions: With a median 37.0 month follow-up, BRL-201 demonstrated durable responses, high median PFS (19.5 months), and a 12-month OS rate of 76.2%. The median OS for responders has not yet been reached. The safety profile was manageable, highlighting the clinical potential of BRL-201. Further data collection is ongoing to establish its clinical value. Clinical trial information: NCT04213469 , NCT05741359 .