Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
Sanofi, Bridgewater, New Jersey, USA.
CPT Pharmacometrics Syst Pharmacol. 2023 Mar;12(3):413-424. doi: 10.1002/psp4.12925. Epub 2023 Feb 6.
T cell interaction in the tumor microenvironment is a key component of immuno-oncology therapy. Glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) is expressed on immune cells including regulatory T cells (Tregs) and effector T cells (Teffs). Preclinical data suggest that agonism of GITR in combination with Fc-γ receptor-mediated depletion of Tregs results in increased intratumoral Teff:Treg ratio and tumor shrinkage. A novel quantitative systems pharmacology (QSP) model was developed for the murine anti-GITR agonist antibody, DTA-1.mIgG2a, to describe the kinetics of intratumoral Tregs and Teffs in Colon26 and A20 syngeneic mouse tumor models. It adequately captured the time profiles of intratumoral Treg and Teff and serum DTA-1.mIgG2a and soluble GITR concentrations in both mouse models, and described the response differences between the two models. The QSP model provides a quantitative understanding of the trade-off between maximizing Treg depletion versus Teff agonism, and offers insights to optimize drug design and dose regimen.
肿瘤微环境中的 T 细胞相互作用是免疫肿瘤治疗的一个关键组成部分。糖皮质激素诱导的肿瘤坏死因子受体（TNFR）相关蛋白（GITR）表达于免疫细胞，包括调节性 T 细胞（Tregs）和效应 T 细胞（Teffs）。临床前数据表明，GITR 激动剂与 Fc-γ 受体介导的 Tregs 耗竭联合使用可导致肿瘤内 Teff:Treg 比值增加和肿瘤缩小。开发了一种新型定量系统药理学（QSP）模型，用于描述鼠抗 GITR 激动剂抗体 DTA-1.mIgG2a 在 Colon26 和 A20 同源小鼠肿瘤模型中的动力学。该模型充分捕捉了两种小鼠模型中肿瘤内 Treg 和 Teff 以及血清 DTA-1.mIgG2a 和可溶性 GITR 浓度的时间曲线，并描述了两种模型之间的反应差异。该 QSP 模型提供了对最大化 Treg 耗竭与 Teff 激动作用之间权衡的定量理解，并为优化药物设计和剂量方案提供了见解。
