CELL INTELLIGENCE · 肿瘤细胞治疗研究

Despite tremendous clinical responses and patient benefit in hematological malignancies, chimeric Antigen Receptor (CAR) T cells have demonstrated limited success in solid tumors. Herein, we have scaled and augmented our previously described murine PBPK-PD model (Singh et al. mAbs, 2020) to characterize cellular kinetics (CK) and anti-tumor activity in patients with solid tumor malignancies. The model was able to integrate (1) differential kinetics of effector- and memory-phenotypes in peripheral blood (PB), solid tumors and other pertinent tissues (n = 8), (2) host-immune system dynamics with or without prior lymphodepletion chemotherapy (LDC) and its impact of CAR-T cell kinetics and (3) antigenic heterogeneity in patients. Model was developed based on digitized individual level CK, categorical antitumor activity and percentage tumor antigen expression dataset from following phase-1 dose-escalation studies: (A) anti-mesothelin CAR-T in multiple cancer indications (n = 15, cohorts w/ and w/o LDC), (B) gavocabtagene autoleucel (n = 7, w/ and w/o LDC) in multiple indications, (C) anti-glypican 3 CAR-T in advanced hepatocellular carcinoma (n = 13, dose-range 0.7-5.18 billion) and (D) anti-PSMA/TGF CAR-T in prostate cancer (n = 10, w/ and w/o LDC). The developed clinical PBPK-PD model was able to simultaneously characterize the CK and categorical anti-tumor longitudinal dataset(s) for each case study while accounting for antigen-expressing tumor burden in each patient. Moreover, model accounted for host-T cell population dynamics post LDC, which competed with CAR-T cell towards overall expansion and persistence post-treatment. Using model simulation, CAR-T cell expansion was found to be dependent on initial tumor burden and antigen positive tumor fraction. The developed PBPK-PD model could be leveraged as an effective tool in future to provide mechanistic understanding on CK-PD behavior of cell therapies targeting solid tumors.