Tisagenlecleucel (CTL019) is an investigational immunotherapy that involves reprogramming a patient's own T cells with a transgene encoding a chimeric antigen receptor to identify and eliminate CD19-expressing cells. We previously reported that CTL019 achieved impressive clinical efficacy in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL), including the expansion and persistence of CTL019 cells, which correlates with response to therapy. Here, we performed formal cellular kinetic analyses of CTL019 in a larger cohort of 103 patients treated with CTL019 in 2 different diseases (ALL and CLL). CTL019 was measured in peripheral blood and bone marrow, using quantitative polymerase chain reaction and flow cytometry. CTL019 levels in peripheral blood typically peaked at 10 to 14 days postinfusion and then declined slowly over time. Patients with complete response (CR)/CR with incomplete count recovery had higher levels of CTL019 in peripheral blood, with greater maximal concentration and area under the curve values compared with nonresponding patients (P < .0001 for each). CTL019 transgene levels were measurable up to 780 days in peripheral blood. CTL019 trafficking and persistence were observed in bone marrow and cerebrospinal fluid. CTL019 expansion correlated with severity of cytokine release syndrome (CRS) and preinfusion tumor burden in pediatric ALL. The results described here are the first detailed formal presentation of cellular kinetics across 2 diseases and highlight the importance of the application of in vivo cellular kinetic analyses to characterize clinical efficacy and CRS severity associated with CTL019 therapy.

中文翻译：

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CTL019在复发/难治性B细胞急性淋巴细胞白血病和慢性淋巴细胞白血病中的细胞动力学

Tisagenlecleucel (CTL019) 是一种研究性免疫疗法，涉及用编码嵌合抗原受体的转基因重新编程患者自身的 T 细胞，以识别和消除表达 CD19 的细胞。我们之前报道过 CTL019 在复发/难治性 B 细胞急性淋巴细胞白血病 (ALL) 和慢性淋巴细胞白血病 (CLL) 患者中取得了令人印象深刻的临床疗效，包括 CTL019 细胞的扩增和持久性，这与治疗反应相关。在这里，我们在 103 名接受 CTL019 治疗的 2 种不同疾病（ALL 和 CLL）患者的更大队列中对 CTL019 进行了正式的细胞动力学分析。使用定量聚合酶链反应和流式细胞术测量外周血和骨髓中的 CTL019。外周血中的 CTL019 水平通常在输注后 10 至 14 天达到峰值，然后随着时间的推移缓慢下降。与无反应患者相比，完全反应 (CR)/CR 且计数恢复不完全的患者外周血中的 CTL019 水平更高，最大浓度和曲线下面积值更大（每个 P < .0001）。CTL019 转基因水平在外周血中可测量长达 780 天。在骨髓和脑脊液中观察到 CTL019 的运输和持久性。CTL019 扩增与儿童 ALL 中细胞因子释放综合征 (CRS) 和输注前肿瘤负荷的严重程度相关。