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690 High safety and efficacy of CRISPR-Based non-viral PD1 locus specific Integrated Anti-CD19 CAR-T cells (BRL-201) in treating relapsed or refractory non-Hodgkin’s lymphoma: first-in-human phase I study
  1. Biao Zheng1,
  2. YongXian Hu2,
  3. Jiqin Zhang1,
  4. Mingming Zhang3,
  5. Wei Li1,
  6. Wenjun Wu2,
  7. Jiazhen Cui2,
  8. Guoqing Wei3,
  9. Bing Du1,
  10. Mingyao Liu1 and
  11. He Huang2
  1. 1BRL Medicine Inc., Shanghai, China
  2. 2The First AffiliatedHospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
  3. 3Zhejiang Province Engineering Laboratory for Stem Cell andImmunity Therapy, Hangzhou, Zhejiang, China
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


Background We developed a novel approach to generate non-viral, genome-specific integrated CAR-T cells through CRISPR/Cas9, thereby breaking through both virus usage and random integration simultaneously. Here, we update the newest data of phase I 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).

Methods Adult patients with r/r B-NHL underwent leukapheresis and a lymphodepletion chemotherapy with cyclophosphamide (500mg/m2, D -3 to -2) and fludarabine (30mg/m2, D -4 to -2) before BRL-201 infusion. Dose escalation are based on 3+3 escalation rule, including three cohorts: 2×106/kg, 4×106/kg, 6×106/kg. The primary endpoint was the incidence of dose-limiting toxicities (DLT) and secondary endpoint was the objective response rate (ORR) at 3 months.

Results Between May 3, 2020 and August 10, 2021, 25 patients with r/r B-NHL were enrolled and 21 received BRL-201 with a median age of 56 years (34–70) and a median of 4 (1–9) prior lines of therapy. Among all the treated patients, 17 patients (93.8%) were diagnosed with disease stage III or IV, and 13 patients (81.3%) were assessed with intermediate to high risk according to IPI or aaIPI score assessment.

As of May 17, 2023, the median follow- up was 29.0 months (21.5–36.2 m). All of 21 (100%) patients had an objective response to BRL-201 and 18 (85.7%) patients had a complete response (CR) as best response (figure 1). 7 patients maintained CR at data cut-off date. The median duration of response(DOR) for all 21 patients was 15.1 months (95%CI: 5.9, NA ) (figure 2A). The median progression free survival (PFS) was 20.8 (95%CI: 8.2, NA) months (figure 2B), while the median overall survival (OS) was not reached, 12-month OS rate was 76.2% (95% CI: 60%, 96.8%) (figure 2C). 14 patients (66.7%) experienced grade 1–2 cytokine release syndrome (CRS) and only one patient received tocilizumab. 4 patients (19.0%) experienced grade 1–2 immune effector cell-associated neurotoxicity syndrome (ICANS). No grade 3–4 CRS and ICANS were observed.

Conclusions This is a first-in-human study of a novel type of non-viral genome specific targeted CAR-T cells in heavily treated r/r B-NHL in China. BRL-201 demonstrated durable response with a median PFS of 20.8 months and 12-month OS rate of 76.2%, and a manageable safety profile. These data continues supporting the compelling clinical benefit-risk profile of BRL-201for r/r B-NHL patients.

Abstract 690 Figure 1

Swimming plots of BRL-201 treatment duration, response and clinical outcomes.

Abstract 690 Figure 2

DOR, PFS and OS.

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