Bristol Myers Squibb, Princeton, NJ, USA.
Certara, Princeton, NJ, USA.
Clin Pharmacokinet. 2021 Dec;60(12):1621-1633. doi: 10.1007/s40262-021-01039-5. Epub 2021 Jun 14.
Lisocabtagene maraleucel (liso-cel) is a CD19-directed, defined composition, 4-1BB chimeric antigen receptor (CAR) T-cell product administered at equal target doses of CD8 and CD4 CAR T cells. Large between-subject variability has been noted with CAR T-cell therapies; patient characteristics might contribute to CAR T-cell expansion variability. We developed a population cellular kinetic model to characterize the kinetics of the liso-cel transgene, via quantitative polymerase chain reaction assessment after intravenous infusion of liso-cel, and to understand covariates that might influence liso-cel kinetics in individual patients.
We employed nonlinear mixed-effects modeling to develop a population cellular kinetic model for liso-cel. The population cellular kinetic analysis was performed using 2524 post-infusion transgene observations from 261 patients with relapsed/refractory large B-cell lymphoma who were treated with a single dose of liso-cel in TRANSCEND NHL 001. Covariates for the analysis included baseline intrinsic factors such as age, baseline disease characteristics, and liso-cel and coadministration factors.
Liso-cel cellular kinetics were well described by a piecewise model of cellular growth kinetics that featured lag, exponential growth, and biexponential decay phases. Population means (95% confidence interval) of lag phase duration, doubling time, time to maximum levels, initial decline half-life, and terminal half-life were 3.27 (2.71-3.97), 0.755 (0.667-0.821), 9.29 (8.81-9.70), 5.00 (4.15-5.90), and 352 (241-647) days, respectively. The magnitude of effect on liso-cel expansion metrics demonstrated that the covariate associations were smaller than the residual between-subject variability in the population.
The covariates tested were not considered to have a meaningful impact on liso-cel kinetics.
NCT02631044.
Lisocabtagene maraleucel（liso-cel）是一种 CD19 靶向、定义明确的组合物，4-1BB 嵌合抗原受体（CAR）T 细胞产品，以相等的 CD8 和 CD4 CAR T 细胞靶剂量给药。CAR T 细胞疗法中已经注意到了很大的个体间变异性；患者特征可能导致 CAR T 细胞扩增的变异性。我们开发了一种群体细胞动力学模型，通过静脉输注 liso-cel 后定量聚合酶链反应评估来描述 liso-cel 转基因的动力学，并了解可能影响个体患者 liso-cel 动力学的协变量。
我们采用非线性混合效应模型为 liso-cel 开发了一个群体细胞动力学模型。使用 TRANSCEND NHL 001 中接受单次 liso-cel 治疗的 261 例复发/难治性大 B 细胞淋巴瘤患者的 2524 个输注后转基因观察值进行群体细胞动力学分析。分析的协变量包括年龄等基线内在因素、基线疾病特征以及 liso-cel 和辅助给药因素。
liso-cel 细胞动力学很好地由细胞生长动力学的分段模型描述，该模型具有滞后、指数增长和双指数衰减阶段。滞后期持续时间、倍增时间、达到最大水平时间、初始下降半衰期和终末半衰期的群体平均值（95%置信区间）分别为 3.27（2.71-3.97）、0.755（0.667-0.821）、9.29（8.81-9.70）、5.00（4.15-5.90）和 352（241-647）天。对 liso-cel 扩增指标的影响程度表明，协变量相关性小于群体间的剩余个体间变异性。
测试的协变量被认为对 liso-cel 动力学没有明显影响。
NCT02631044。
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