Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia.
Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia.
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DOI：
10.1158/1078-0432.ccr-18-0758
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发表时间：
2018-12-15
期刊：
影响因子：
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通讯作者：
Maude SL
中科院分区：
文献类型：
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作者：
Mueller KT;Waldron E;Grupp SA;Levine JE;Laetsch TW;Pulsipher MA;Boyer MW;August KJ;Hamilton J;Awasthi R;Stein AM;Sickert D;Chakraborty A;Levine BL;June CH;Tomassian L;Shah SS;Leung M;Taran T;Wood PA;Maude SL
Tisagenlecleucel是一种抗CD19嵌合抗原受体(CAR19)T细胞疗法，被批准用于治疗儿童和年轻人的复发/难治性(r/r)B细胞急性淋巴细胞白血病(B-ALL)。我们在儿科B-ALL的两项研究(Eliana和Ensign)中，评估了组织凝集素的细胞动力学、患者因素、体液免疫原性和制造属性对其动力学的影响，并对79名患者进行了有效性、安全性和药效学终点的暴露反应分析。用定量聚合酶链式反应定量组织凝集素转基因水平，应答者(N=62)外周血中组织凝集素扩增的≈是无应答者(N=8；几何平均Cmax和AUC0-28d分别高74%和104%)的2倍，持续时间可在有反应的患者中测量到超过2年。Cmax随着细胞因子释放综合征(CRS)的发生和严重程度的加重而增加。在用于管理CRS的tocilizumab之后，Tisagenlecleucel继续扩大并持续存在。与持续临床应答的患者相比，B细胞在6个月内恢复的患者有更早的转基因丢失。在评估的整个剂量范围内都出现了临床反应(患者≤50千克：0.2至5.0×106/千克；患者>；50千克：0.1至2.5×108个CAR阳性活T细胞)，与剂量和安全性无关。无论是预先存在的还是治疗诱导的抗尿cAR19抗体都不影响持久性或临床反应。对组织凝集素的反应与在较大剂量范围内扩张的增加有关。这些结果强调了细胞动力学在了解嵌合抗原受体T细胞治疗反应的决定因素方面的重要性。
Tisagenlecleucel is an anti-CD19 chimeric antigen receptor (CAR19) T-cell therapy approved for the treatment of children and young adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL). We evaluated the cellular kinetics of tisagenlecleucel, the effect of patient factors, humoral immunogenicity, and manufacturing attributes on its kinetics, and exposure-response analysis for efficacy, safety and pharmacodynamic endpoints in 79 patients across two studies in pediatric B-ALL (ELIANA and ENSIGN). Using quantitative polymerase chain reaction to quantify levels of tisagenlecleucel transgene, responders (N = 62) had ≈2-fold higher tisagenlecleucel expansion in peripheral blood than nonresponders (N = 8; 74% and 104% higher geometric mean Cmax and AUC0–28d, respectively) with persistence measurable beyond 2 years in responding patients. Cmax increased with occurrence and severity of cytokine release syndrome (CRS). Tisagenlecleucel continued to expand and persist following tocilizumab, used to manage CRS. Patients with B-cell recovery within 6 months had earlier loss of the transgene compared with patients with sustained clinical response. Clinical responses were seen across the entire dose range evaluated (patients ≤50 kg: 0.2 to 5.0 × 106/kg; patients >50 kg: 0.1 to 2.5 × 108 CAR-positive viable T cells) with no relationship between dose and safety. Neither preexisting nor treatment-induced antimurine CAR19 antibodies affected the persistence or clinical response. Response to tisagenlecleucel was associated with increased expansion across a wide dose range. These results highlight the importance of cellular kinetics in understanding determinants of response to chimeric antigen receptor T-cell therapy.