Conventional CAR-T cell treatment is expensive, time-consuming, and has a risk of cancer because it is frequently virus-based. In order to get around these limitations, a novel non-viral CRISPR/Cas9-mediated technique for producing genome-specific integrated CAR-T cells is developed. BRL Medicine is now developing BRL-201, a new anti-cd20/cd19 bi-specific car T-cell therapy, to treat NHL.

A phase I/II of BRL-201 (NCT05741359) is ongoing with a large-scale and multi-center design to further evaluate BRL-201 antitumor activity in lower dose levels. During the EHA 2024 conference, long term follow up data of the trial was presented. BRL-201 study is sponsored by Bioray Laboratories and the collaborator of the study is First Affiliated Hospital of Zhejiang University.

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. Primary endpoint: incidence of dose-limiting toxicities (DLT). Secondary endpoint: proportion of patients achieving an objective response at 3 months as assessed by investigators. 

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.

Efficacy: The median follow-up was 38.0 months (95% CI: 34.76–41.24 months) as of February 10, 2024. All 21 patients showed an objective response, with 18 (85.7%) achieving complete response (CR). CR was maintained by seven patients at data cut-off. The median duration of response (DOR) was 18.6 months (95% CI: 4.10–33.10), with a median progression-free survival (PFS) of 19.5 months (95% CI: 5.15–33.86). The 12-month overall survival (OS) rate was 76.2% (95% CI: 60%–96.8%). The estimated median OS was 38.5 months (95% CI: 30.12–46.88).

Safety: 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.

KOL insights

“The administration of CAR T-cell therapy in the outpatient setting was deemed feasible and safe in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), according to findings from an exploratory analysis of real-world outpatient effectiveness shared during the 2024 EHA Congress,” – MD, United States

Conclusion 

BRL-201 is world's first autologous CAR-T cell product to eliminates the PD1 gene without the use of viral vectors and accomplishes targeted genome integration at the PD1 location. BRL-201 is based on the non-viral site-specific integrated CAR-T platform (Quikin CART®) independently developed by BRL Medicine. 

Advantages of this approach include: 

• CAR sequence is precisely inserted into a specific site, avoiding the risk of tumorigenesis caused by random insertion; 

• CAR knock-in and PD1 knock-out can be completed in one step, allowing the continuous expression of CAR and releasing the inhibition of T cell function; 

• Shortened preparation time using a simpler and more cost-effective process

On December 14, 2022, the National Medical Products Administration (NMPA)/ Center for Drug Evaluation (CDE) approved the CAR-T product's investigational new drug (IND), allowing it to formally enter clinical stage I.

The study's data revealed that BRL-201 exhibited strong responses, a high median PFS (19.5 months), and a 12-month OS rate of 76.2%, with a median follow-up of 38.0 months. The estimated median OS was 38.5 months. BRL-201 also exhibited a manageable safety profile.  More information is being gathered to determine its therapeutic use.