Mechanistic data-informed multiscale quantitative systems pharmacology modeling framework enables the clinical translation and efficacy assessment of CAR-T therapy in solid tumors
Siyuan Yang, Wenjie Wang, Qi Rao, Yiyang Xu, Sujie Zhang, Yuchen Qu, Qiu-Chuan Zhuang, Jie Mao, Laura Sun, Dong Geng, Da Xu, Chen Zhao
Abstract
BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy represents an innovative and potentially revolutionary modality in cancer treatment. Despite their great success in treating blood cancers, CAR-T therapies exhibit significantly lower effectiveness in treating solid tumors. Moreover, the preclinical-to-clinical translation of CAR-T therapies targeting solid tumors is still a challenging task because of their unique "live cell" nature and the substantial variability in patients' pathophysiology. METHODS: We have developed a multiscale quantitative systems pharmacology (QSP) model to facilitate the clinical translation of CAR-T therapies in solid tumors. Our mechanistic modeling framework integrates the essential biological features that impact CAR-T cell fate and antitumor cytotoxicity, from cell-level CAR-antigen interaction and activation, to in vivo CAR-T biodistribution, proliferation and phenotype transition, and finally to clinical-level patient tumor heterogeneity and response variability. This modeling framework has been calibrated and validated by multimodal experimental data including published preclinical and clinical data of various CAR-T products and original preclinical data of a novel claudin18.2-targeted CAR-T product LB1908. RESULTS: We demonstrated the general utility of this framework in facilitating clinical translation and characterizing the paired cellular kinetics-cytotoxicity response of different antigen-targeting solid tumor CAR-T cell therapies. As an example, we generated model-based virtual patients and prospectively simulated the response to claudin18.2-targeted CAR-T therapies under different dosing strategies, including step-fractionated dosing and convenient flat dose-based regimens, to inform future clinical trial implementation. CONCLUSIONS: Our translational QSP platform offers an innovative pathway to integrate multiscale knowledge and inform clinical decision-making of novel solid tumor-targeting CAR-T therapies.