The development of mechanism-based, multiscale pharmacokinetic-pharmacodynamic (PK-PD) models for chimeric antigen receptor (CAR)-T cells is needed to enable investigation of in vitro and in vivo correlation of CAR-T cell responses and to facilitate preclinical-to-clinical translation. Toward this goal, we first developed a cell-level in vitro PD model that quantitatively characterized CAR-T cell-induced target cell depletion, CAR-T cell expansion and cytokine release. The model accounted for key drug-specific (CAR-affinity, CAR-densities) and system-specific (antigen densities, E:T ratios) variables and was able to characterize comprehensive in vitro datasets from multiple affinity variants of anti-EGFR and anti-HER2 CAR-T cells. Next, a physiologically based PK (PBPK) model was developed to simultaneously characterize the biodistribution of untransduced T-cells, anti-EGFR CAR-T and anti-CD19 CAR-T cells in xenograft -mouse models. The proposed model accounted for the engagement of CAR-T cells with tumor cells at the site of action. Finally, an integrated PBPK-PD relationship was established to simultaneously characterize expansion of CAR-T cells and tumor growth inhibition (TGI) in xenograft mouse model, using datasets from anti-BCMA, anti-HER2, anti-CD19 and anti-EGFR CAR-T cells. Model simulations provided potential mechanistic insights toward the commonly observed multiphasic PK profile (i.e., rapid distribution, expansion, contraction and persistence) of CAR-T cells in the clinic. Model simulations suggested that CAR-T cells may have a steep dose-exposure relationship, and the apparent Cmax upon CAR-T cell expansion in blood may be more sensitive to patient tumor-burden than CAR-T dose levels. Global sensitivity analysis described the effect of other drug-specific parameters toward CAR-T cell expansion and TGI. The proposed modeling framework will be further examined with the clinical PK and PD data, and the learnings can be used to inform design and development of future CAR-T therapies.

中文翻译：

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使用多尺度系统PK-PD模型开发CAR亲和力，抗原丰度，肿瘤细胞耗竭和CAR-T细胞扩增之间的定量关系。

需要开发用于嵌合抗原受体（CAR）-T细胞的基于机制的多尺度药代动力学（PK-PD）模型，以便能够研究CAR-T细胞反应的体外和体内相关性并促进临床前研究。到临床翻译。为了实现这一目标，我们首先开发了一种细胞水平的体外PD模型，该模型定量表征了CAR-T细胞诱导的靶细胞耗竭，CAR-T细胞扩增和细胞因子释放。该模型考虑了关键的药物特异性（CAR亲和力，CAR密度）和系统特异性（抗原密度，E：T比）变量，并能够从抗EGFR和抗EGFR的多个亲和力变体中表征综合的体外数据集-HER2 CAR-T细胞。下一个，建立了基于生理的PK（PBPK）模型，以同时表征异种移植小鼠模型中未转导的T细胞，抗EGFR CAR-T和抗CD19 CAR-T细胞的生物分布。提出的模型说明了作用部位CAR-T细胞与肿瘤细胞的结合。最后，使用来自抗BCMA，抗HER2，抗CD19和抗EGFR CAR的数据集，建立了整合的PBPK-PD关系以同时表征异种移植小鼠模型中CAR-T细胞的扩增和肿瘤生长抑制（TGI）。 -T细胞。模型仿真为临床上常见的CAR-T细胞多相PK分布（即快速分布，扩展，收缩和持久性）提供了潜在的力学见解。模型仿真表明，CAR-T细胞可能具有陡峭的剂量-暴露关系，并且血液中CAR-T细胞扩增后的表观Cmax可能比CAR-T剂量水平对患者的肿瘤负担更为敏感。全球敏感性分析描述了其他药物特异性参数对CAR-T细胞扩增和TGI的影响。拟议的建模框架将通过临床PK和PD数据进行进一步检查，这些经验可用于为未来CAR-T疗法的设计和开发提供信息。