Bench‐to‐bedside translation of chimeric antigen receptor (CAR) T cells using a multiscale systems pharmacokinetic‐pharmacodynamic model: A case study with anti‐BCMA CAR‐T

作者：Aman P. Singh, Wenbo Chen, Xirong Zheng, Hardik Mody, Thomas Carpenter, Alice Zong, Donald Heald · 发表于：CPT Pharmacometrics & Systems Pharmacology · 年份：2021 · DOI：10.1002/psp4.12598 · 被引用次数：51 · 研究领域：CAR-T cell therapy research、Advancements in Semiconductor Devices and Circuit Design、Monoclonal and Polyclonal Antibodies Research

Despite tremendous success of chimeric antigen receptor (CAR) T cell therapy in clinical oncology, the dose-exposure-response relationship of CAR-T cells in patients is poorly understood. Moreover, the key drug-specific and system-specific determinants leading to favorable clinical outcomes are also unknown. Here we have developed a multiscale mechanistic pharmacokinetic (PK)-pharmacodynamic (PD) model for anti-B-cell maturation antigen (BCMA) CAR-T cell therapy (bb2121) to characterize (i) in vitro target cell killing in multiple BCMA expressing tumor cell lines at varying effector to target cell ratios, (ii) preclinical in vivo tumor growth inhibition and blood CAR-T cell expansion in xenograft mice, and (iii) clinical PK and PD biomarkers in patients with multiple myeloma. Our translational PK-PD relationship was able to effectively describe the commonly observed multiphasic CAR-T cell PK profile in the clinic, consisting of the rapid distribution, expansion, contraction, and persistent phases, and accounted for the categorical individual responses in multiple myeloma to effectively calculate progression-free survival rates. Preclinical and clinical data analysis revealed comparable parameter estimates pertaining to CAR-T cell functionality and suggested that patient baseline tumor burden could be more sensitive than dose levels toward overall extent of exposure after CAR-T cell infusion. Virtual patient simulations also suggested a very steep dose-exposure-response relati...