Axicabtagene ciloleucel（axi-cel，Yescarta）是一种自体、抗 CD19、嵌合抗原受体 (CAR) T 细胞疗法，被批准用于复发性和难治性非霍奇金淋巴瘤患者。 CAR-T 疗法观察到细胞动力学存在显着的个体间差异，但影响 CAR-T 细胞动力学的因素仍知之甚少。这项工作报告了 axi-cel 在复发和难治性非霍奇金淋巴瘤患者中的群体细胞动力学模型，并研究了协变量对 CAR-T 暴露的早期和晚期动力学阶段的影响。群体细胞动力学模型（NONMEM® 7.4 版） ）的 axi-cel 是使用来自 410 名患者（2050 个转基因观察）的数据开发的，这些数据是在非霍奇金淋巴瘤患者（ZUMA-1、ZUMA-5、和 ZUMA-7 临床研究）。对一大组协变量进行了评估，以解读 CAR-T 细胞动力学的变异性，包括患者特征、产品特征和疾病类型。Axi-cel 细胞动力学通过以指数生长期为特征的细胞生长动力学分段模型得到了很好的描述随后是三相衰退阶段，包括长期持续阶段。最终的细胞动力学模型保留了 CAR-T 细胞制造过程中的体外倍增时间和输注的 T 细胞总数作为影响生长期持续时间的协变量，然而，这并没有显着影响最大浓度、浓度-时间下的面积前 28 天的曲线，或长期持续。在最大浓度和接受托珠单抗和/或皮质类固醇的概率之间观察到统计学上显着的关系。本研究中考虑的协变量没有发现能够显着且实质性地预测 axi-cel 的暴露情况。托珠单抗和类固醇的使用与最大浓度相关，但它们被反应性地用于治疗与较高最大浓度相关的毒性。进一步的 CAR-T 动力学分析应考虑其他因素来解释观察到的细胞动力学变异性或帮助建立剂量-暴露关系。NCT02348216 (ZUMA-1)、NCT03105336 (ZUMA-5) 和 NCT03391466 (ZUMA-7)。© 2024 年。作者获得 Springer Nature Switzerland AG 的独家许可。

Axicabtagene ciloleucel (axi-cel, Yescarta) is an autologous, anti-CD19, chimeric antigen receptor (CAR) T-cell therapy approved for patients with relapsed and refractory non-Hodgkin's lymphoma. Substantial inter-individual variability in cellular kinetics has been observed with CAR-T therapies and factors impacting CAR-T cellular kinetics remain poorly understood. This work reports a population cellular kinetic model of axi-cel in relapsed and patients with refractory non-Hodgkin's lymphoma and investigated the impact of covariates on early and late kinetic phases of CAR-T exposure.A population cellular kinetic model (NONMEM® version 7.4) for axi-cel was developed using data from 410 patients (2050 transgene observations) after a single intravenous infusion of 2 × 106 anti-CD19 CAR+ T cells/kg in patients with non-Hodgkin's lymphoma (ZUMA-1, ZUMA-5, and ZUMA-7 clinical studies). A large panel of covariates was assessed to decipher the variability of CAR-T cell kinetics including patient characteristics, product characteristics, and disease types.Axi-cel cellular kinetics were well described by a piecewise model of cellular growth kinetics characterized by an exponential growth phase followed by a triphasic decline phase including a long-term persistence phase. The final cellular kinetic model retained in vitro doubling time during CAR-T cell manufacturing and total number of T cells infused as covariates impacting the duration of the growth phase, which, however, did not substantially influence maximum concentration, area under the concentration-time curve over the first 28 days, or long-term persistence. A statistically significant relationship was observed between maximum concentration and the probability to receive tocilizumab and/or corticosteroids.No covariates considered in this study were found to significantly and substantially predict the exposure profile of axi-cel. Tocilizumab and steroid use were related to maximum concentration, but they were used reactively to treat toxicities that are associated with a higher maximum concentration. Further CAR-T kinetic analyses should consider additional factors to explain the observed variability in cellular kinetics or help establish a dose-exposure relationship.NCT02348216 (ZUMA-1), NCT03105336 (ZUMA-5), and NCT03391466 (ZUMA-7).© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.