CRISPR CAR Therapy Shows 100% ORR in NHL in Chinese Trial

Biao Zheng, PhD

BRL-201 CRISPR-/Cas9-based chimeric antigen receptor (CAR) T-cell therapy yielded a 100% overall response rate (ORR) in 21 patients with relapsed/refractory (r/r) non-Hodgkin lymphoma treated in a phase 1/2 clinical trial in China (NCT04213469).

Data from the trial, updated as of May 2023, were presented at The Society for Immunotherapy of Cancer’s (SITC) 38th Annual Meeting, held November 1-5 in San Diego, California, by Biao Zheng, PhD, chief executive officer, BRL Medicine.

“Unlike current viral-based or transposon-based CAR T-cells in which integration occurs randomly and with various copy numbers, yielding a very heterogenous CAR T population, in our approach, the CAR sequence precisely integrates into the PD-1 site, so you can generate a very homogenous population. [This approach] has shown a great efficacy and safety profile in earlier and ongoing clinical trials,” Zheng said during his presentation.

The trial’s primary endpoint is the incidence of dose-limiting toxicities, and its secondary endpoint is the ORR at 3 months with the CD19-targeting CAR T-cell therapy. The trial treated patients with diffuse large B-cell lymphoma (DLBCL; n = 17), mantle cell lymphoma (n = 2); B-cell lymphoblastic lymphoma (B-LBL; n = 1), and follicular lymphoma (n = 1). These participants had a median age of 56 years (range, 34–70) and a median of 4 prior lines of therapy (range, 1–9). Seventeen (93.8%) were diagnosed with disease stage 3 or 4, and 13 patients (81.3%) were assessed with intermediate to high risk according to International Prognostic Index (IPI) or age-adjusted IPI scores.

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The participants underwent leukapheresis and lymphodepletion chemotherapy with cyclophosphamide and fludarabine before infusion of dose escalating 2×10⁶/kg (n = 12), 4×10⁶/kg (n = 3), or 6×10⁶/kg (n = 3) BRL-201. Three patients received 0.56 to 0.8x10⁶/kg cells.

As of the data cutoff date, median follow-up was 29.0 months (range, 21.5-36.2) and all patients responded to BRL-201 treatment. Most patients (n = 18, 85.7%) had a complete response (CR), 7 of which have maintained a CR. The median duration of response was 15.1 months (95% CI, 5.9 - not applicable [NA]), median progression free survival was 20.8 months (95% CI, 8.2-NA), and median overall survival (OS) was not reached. Twelve-month OS rate was 76.2% (95% CI, 60-96.8).

By dose level, CR rate was 83.3% (2×10⁶/kg), 66.7% (4×10⁶/kg), 100% (6×10⁶/kg), and 100% (0.56-0.8 ×10⁶/kg). By disease, CR rate was 100% in patients with MCL, B-LBL, and FL, and was 82.4% in patients with DLBCL. During his presentation, Zheng pointed out that BRL-201 induced enduring, continuing CRs in 3 of 4 patients with PD-L1 expression over 50%.

In terms of safety, over half (n = 14; 66.7%) of patients experienced grades 1-to-2 cytokine release syndrome (CRS) and 1 patient received tocilizumab. Four patients experienced mild grades 1-to-2 immune effector cell-associated neurotoxicity syndrome (ICANS) and no patients experienced serious grade CRS or ICANS.

“BRL-201 is a CD19-targeting CAR T-cell product with nonviral, site-specific integrated CAR-T that aims to reduce potential risk of virus usage, to simplify the manufacture process, and to decrease the expense... of CAR T-cell manufacture,” Zheng said. “Currently, to evaluate BRL-201 antitumor activity at lower dose ranges, a phase 1/2 clinical trial (NCT05741359) is ongoing with a larger scale, multicenter design.”

Click here to read more coverage of the 2023 SITC meeting.

REFERENCE

Zhang B, Hu Y, Zhang J, et al. 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. Presented at: SITC 38th Annual Meeting; November 1-5, 2023; San Diego, California. Abstract 690.