Annesley Colleen, Seidel Kristy D, Wu Qian, Summers Corinne, Wayne Alan S, Pulsipher Michael A, Agrawal Anurag K, Brown Christopher T, Mgebroff Stephanie, Lindgren Catherine G, Rawlings-Rhea Stephanie D, Huang Wenjun, Wilson Ashley, Jensen Michael C, Park Julie R, Gardner Rebecca A
Seattle Children's Therapeutics, United States.
Seattle Children's Therapuetics, United States.
Blood. 2025 Apr 15. doi: 10.1182/blood.2025028359.
This study reports outcomes of PLAT-02, a phase 2 trial of SCRI-CAR19, a second-generation CAR T-cell product with FMC63 scFv and 41BB costimulation, in pediatric and young adult patients with B-cell acute lymphoblastic leukemia; and PLAT-03, a companion study evaluating exogenous CD19 antigen stimulation with serial infusions of T cells expressing truncated CD19, T-cell antigen presenting cells (T-APCs). The efficacy cohort of PLAT-02 (n=72 patients, median age 12.5 years) received fludarabine/cyclophosphamide lymphodepletion followed by a dose of 1X106 CAR+ T cells/kg. MRD-negative complete remission rate was 89%. Leukemia free survival (LFS) with 95% CI at 1 and 2 years was 0.71 (0.58, 0.81) and 0.64 (0.51, 0.75). Patients with low disease burden had significantly higher 1-year LFS (0.91 vs. 0.42). Rapid in vivo contraction of CAR T cells after infusion was associated with CAR loss within six months compared to those without rapid contraction (57% vs. 19%, respectively). Most common grade 3/4 adverse events included cytokine release syndrome in 13% and neurotoxicity in 16%. The companion pilot, PLAT-03, enrolled 26 patients, and 19 received T-APCs. Neither cytokine-release syndrome nor neurotoxicity were observed after T-APC infusion. T-APC infusion in patients improved persistence (P=0.03) with rapid CAR T-cell contraction was associated with decreased early CAR loss (20% with T-APC vs. 57% without). Further exploration of serial artificial CD19 antigen exposure is warranted based on these pilot results. PLAT-02 (NCT02028455) and PLAT-03 (NCT03186118).
本研究报告了PLAT-02试验的结果，该试验是针对患有B细胞急性淋巴细胞白血病的儿科和年轻成年患者开展的SCRI-CAR19的2期试验，SCRI-CAR19是一种具有FMC63单链抗体片段（scFv）和4-1BB共刺激的第二代嵌合抗原受体（CAR）T细胞产品；以及PLAT-03试验，这是一项配套研究，评估通过连续输注表达截短型CD19的T细胞（即T细胞抗原呈递细胞，T-APC）进行外源性CD19抗原刺激的效果。PLAT-02试验的疗效队列（n = 72例患者，中位年龄12.5岁）接受了氟达拉滨/环磷酰胺淋巴细胞清除预处理，随后给予1×10⁶个CAR⁺T细胞/kg的剂量。微小残留病（MRD）阴性完全缓解率为89%。1年和2年的无白血病生存率（LFS）及95%置信区间分别为0.71（0.58，0.81）和0.64（0.51，0.75）。疾病负担低的患者1年LFS显著更高（0.91对0.42）。与未快速收缩的患者相比，输注后CAR T细胞在体内快速收缩与6个月内CAR丢失相关（分别为57%对19%）。最常见的3/4级不良事件包括13%的细胞因子释放综合征和16%的神经毒性。配套的PLAT-03试验招募了26例患者，其中19例接受了T-APC治疗。输注T-APC后未观察到细胞因子释放综合征和神经毒性。在CAR T细胞快速收缩的患者中，输注T-APC可改善细胞持久性（P = 0.03），且与早期CAR丢失减少相关（接受T-APC治疗的患者为20%，未接受治疗的患者为57%）。基于这些初步结果，有必要进一步探索连续人工CD19抗原暴露的作用。PLAT-02（NCT02028455）和PLAT-03（NCT03186118）。
