Early phase I study of non-viral CD19/CD22/BCMA tri-targeting JL-Lightning-CAR-T in relapsed/refractory B-cell non-Hodgkin's lymphoma.

Abstract

e14521 Background: Research indicates that CAR-T cell proliferation and persistence correlates with clinical responses, particularly in hematological malignancies. CAR-T cell stemness and exhaustion levels are determinants of in vivo expansion and persistence. The first in human pilot study evaluated CD19/CD22/BCMA tri-targeting CAR-T cells, first using an innovative non-viral JL-Lightning-CAR-T process to manufacture just in 6 to 30 hours, to enhance CAR-T stemness, in vivo proliferation and improve clinical efficacy of hematological malignancies therapy (NCT06446128). Methods: A single-arm, open-label, dose escalating study was designed and carried out to evaluate the safety and preliminary efficacy of non-viral CD19/CD22/BCAM tri-targeting JL-Lightning-CAR-T cells. Study enrolled 7 patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) to Dec. 2024. Patients received a single infusion of CAR-T cells at two very low dose levels (DL1: 5×10⁴ cells/kg, DL2: 1×10⁵ cells/kg) following lymphodepletion (Flu 30 mg/m²/day, Cy 300 mg/m²/day) for 2-3 days, based on a 3+3 dose escalation design. Results: 7 patients of rrNHL were enrolled with median age 66 years (range 54-75) and median prior therapy lines as 3 (range 3-5). All lymphoma tumor biopsy expressed CD19 and CD22, with 6/7 expressing BCMA. Median baseline tumor volume was 4504.5 mm² (range 174.6-7577.7). Efficacy: Patients received DL1 and DL2 of CD19/CD22/BCAM tri-targeting JL-Lightning-CAR-T cells. In DL1 group, four rrDLBCL patients obtained objective response (ORR 100%, 4/4), with three patient achieving complete response (CRR 75%, 3/4). In DL2 group, two rrDLBCL and one rrMCL patients obtained objective response (ORR 100%, 3/3). The durability of the response remains to be observed through continued follow-up. Pharmacokinetics: JL-Lightning-CAR-T cells administered as 1/40-1/20 dose of conventional CAR-T and showed the strong capacity of proliferation. Median CAR-T Cmax reached to 2117 cells/µL (range 332-39253), detectable for over 3 months; Median CAR-T percentage in circulation reached 81% (range 58%-92%). The median time to Cmax was 14 days. Safety: Grade 1 CRS in 100% (7/7) of patients; no ≥Grade 2 CRS. ICANs at Grade 1 was observed in 42.8% (3/7) of patients, one patient happened Grade 3 ICANs, which resolved within 1 day with corticosteroids. All patients experienced Grade ≥3 hematologic toxicities were reversible with supportive care. No dose-limiting toxicity observed. All patients continue to be monitored for safety and efficacy. Conclusions: CD19/CD22/BCMA tri-targeting CAR-T cells were well-tolerated with no DLT observed in the explored dose levels. The innovative non-viral tri-targeting JL-Lightning CAR-T demonstrated robust proliferative capacity and promising antitumor potential. Further investigations into safety and efficacy are warranted. Clinical trial information: NCT06446128 .