Huang Weize, Li Junyi, Liao Michael Z, Liu Stephanie N, Yu Jiajie, Jing Jing, Kotani Naoki, Kamen Lynn, Guelman Sebastian, Miles Dale R
Genentech Inc., South San Francisco, California, USA.
Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
Clin Pharmacol Ther. 2022 Nov;112(5):968-981. doi: 10.1002/cpt.2509. Epub 2022 Jan 21.
Adoptive cell therapies (ACTs) have shown transformative efficacy in oncology with five US Food and Drug Administration (FDA) approvals for chimeric antigen receptor (CAR) T-cell therapies in hematological malignancies, and promising activity for T cell receptor T-cell therapies in both liquid and solid tumors. Clinical pharmacology can play a pivotal role in optimizing ACTs, aided by modeling and simulation toolboxes and deep understanding of the underlying biological and immunological processes. Close collaboration and multilevel data integration across functions, including chemistry, manufacturing, and control, biomarkers, bioanalytical, and clinical science and safety teams will be critical to ACT development. As ACT is comprised of alive, polyfunctional, and heterogeneous immune cells, its overall physicochemical and pharmacological property is vastly different from other platforms/modalities, such as small molecule and protein therapeutics. In this review, we first describe the unique kinetics of T cells and the appropriate bioanalytical strategies to characterize cellular kinetics. We then assess the distinct aspects of clinical pharmacology for ACTs in comparison to traditional small molecule and protein therapeutics. Additionally, we provide a review for the five FDA-approved CAR T-cell therapies and summarize their properties, cellular kinetic characteristics, dose-exposure-response relationship, and potential baseline factors/variables in product, patient, and regimen that may affect the safety and efficacy. Finally, we probe into existing empirical and mechanistic quantitative techniques to understand how various modeling and simulation approaches can support clinical pharmacology strategy and propose key considerations to be incorporated and explored in future models.
过继性细胞疗法(ACTs)在肿瘤学领域已显示出变革性疗效,美国食品药品监督管理局(FDA)已批准了五种嵌合抗原受体(CAR)T细胞疗法用于血液系统恶性肿瘤,并且T细胞受体T细胞疗法在液体和实体瘤中也展现出了有前景的活性。临床药理学在优化ACTs方面可发挥关键作用,这得益于建模与模拟工具箱以及对潜在生物学和免疫过程的深入理解。跨职能部门(包括化学、生产和控制、生物标志物、生物分析以及临床科学与安全团队)的紧密协作和多层次数据整合对于ACT的开发至关重要。由于ACT由活的、多功能且异质性的免疫细胞组成,其整体物理化学和药理学特性与其他平台/剂型(如小分子和蛋白质疗法)有很大不同。在本综述中,我们首先描述T细胞独特的动力学以及用于表征细胞动力学的合适生物分析策略。然后,我们评估ACTs与传统小分子和蛋白质疗法相比临床药理学的不同方面。此外,我们对FDA批准的五种CAR T细胞疗法进行综述,并总结它们的特性、细胞动力学特征、剂量-暴露-反应关系以及产品、患者和治疗方案中可能影响安全性和疗效的潜在基线因素/变量。最后,我们探究现有的经验性和机制性定量技术,以了解各种建模和模拟方法如何支持临床药理学策略,并提出在未来模型中应纳入和探索的关键考虑因素。
Clin Pharmacol Ther. 2022-11
Clin Pharmacol Ther. 2024-6
Adv Drug Deliv Rev. 2022-9
Clin Pharmacol Ther. 2019-1
Acta Biomater. 2020-6
Int J Nanomedicine. 2025-4-16
CPT Pharmacometrics Syst Pharmacol. 2023-11
CPT Pharmacometrics Syst Pharmacol. 2023-11
Cancers (Basel). 2022-11-14
Clin Pharmacol Drug Dev. 2022-10
Pharmaceut Med. 2022-10
AAPS J. 2021-5-3
Clin Pharmacol Ther. 2021-3
Cytometry B Clin Cytom. 2021-3
Front Mol Biosci. 2020-5-15