OA-07: Phase I Study of BCMA CAR-T Using Instant Manufacturing Platform or Traditional Production Process for Relapsed/Refractory Multiple Myeloma Therapy

Introduction: Although chimeric antigen receptor (CAR)-T cell has revolutionized relapsed/refractory (r/r) multiple myeloma (MM) therapy, critical problems including tumor relapse, long vein-to-vein time, insufficient production capacity, and high cost need to be tackled. Traditional production process of autologous CAR-T (named TraditionCART) occupied 9-14 days, resulting in over 3 weeks of vein-to-vein time, high cost, and more seriously, disease progression during the production period. Here a fourth-generation BCMA CAR-T was designed, and manufactured using Instant Manufacturing Platform (named InstanCART) to shorten the production period and optimize the T cell function. Pre-clinical studies confirmed that InstanCART was rich in low differentiated T cells and showed more durable antitumor efficacy compared with TraditionCART.

Methods: A phase 1 clinical trial (NCT04537442) was launched to evaluate the safety and efficacy of the TraditionCART and InstanCART for treating r/r MM. Patients (pts) received a single infusion of TraditionCART at the dose of 1×106/kg CAR-T cells, or InstanCART at the dose of 2×107 T cells. The primary objectives were safety and toxicity, and the secondary objectives were efficacy and pharmacokinetic profile. Expansion of CAR-T cells in pts was evaluated using flow cytometry analysis of peripheral blood.

Results: As of May 2023, 22 pts received CAR-T infusion and finished at least 1-month follow-up, with 15 pts in TraditionCART group and 7 pts in InstanCART group. No ≥grade 3 neurotoxicity and cytokine release syndromes (CRS) were observed in both groups. TraditionCART therapy caused grade 1-2 CRS in 12/15 pts (80%), neurotoxicity in 1/15 pt (7%) and led to ≥grade 3 adverse events including thrombocytopenia (9/15, 60%), neutropenia (14/15, 93%), anemia (10/15, 67%), creatinine increased (1/15, 7%), hepatic enzymes increased (2/15, 13%), and sepsis (1/15, 7%). Meanwhile, InstanCART therapy induced grade 1-2 CRS in 7/7 pts (100%), neurotoxicity in 1/7 pt (14%), and also caused ≥grade 3 adverse events including thrombocytopenia (6/7, 86%), neutropenia (6/7, 86%), anemia (2/7, 29%), and hepatic enzymes increased (3/15, 43%). The best overall response rate (ORR) for TraditionCART was 93% (14/15), including 8sCR, 2CR, 2VGPR, 2PR and 1SD. In contrast, the best ORR for InstanCART was 100%, including 3sCR, 1VGPR and 3PR. The expansion and duration of InstanCART (Cmax=297×107/L, AUC0-28d=2854×107/L) were dramatically higher than that of TraditionCART (Cmax=59.1×107/L, AUC0-28d=708.6×107/L). There was no statistically significant difference in progression-free survival and overall survival between InstanCART and TraditionCART.

Conclusions: InstanCART was well tolerated, and showed non-inferior efficacy and more encouraging pharmacokinetic profile compared with TraditionCART for r/r MM therapy. The clinical study is ongoing, and durable efficacies will be evaluated during long-term follow-up.