Development of a Multiscale Mechanistic Modelling Framework Integrating Differential Cellular Kinetics of CAR-T Cell Subsets and Immunophenotypes in Cancer Patients

• Published in: CPT: pharmacometrics and systems pharmacology Vol. 12; no. 9; pp. 1285 - 1304
• Main Authors: Salem, Ahmed M, Mugundu, Ganesh M, Singh, Aman P
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.09.2023; John Wiley and Sons Inc; Wiley
• Subjects: Antigens; Cytotoxicity; Datasets; Digitization; Drug dosages; Flow cytometry; Kinetics; Pharmacodynamics; Polymerase chain reaction; Stem cells
• ISSN: 2163-8306; 2163-8306
• DOI: 10.1002/psp4.13009

Chimeric antigen receptor (CAR) T-cell subsets and immunophenotypic composition of the pre-infusion product, as well as their longitudinal changes following infusion, are expected to affect CAR-T cell expansion, persistence, and clinical outcomes. Herein, we sequentially evolved our previously described cellular kinetic-pharmacodynamic (CK-PD) model to incorporate CAR-T cell product-associated attributes by utilizing published preclinical and clinical datasets from two affinity variants (FMC63 and CAT19 scFv) anti-CD19 CAR-T cells. In step 1, a unified cell-level PD model was used to simultaneously characterize the in vitro killing datasets of two CAR-Ts against CD19+ cell lines at varying effector: target (E: T) ratios. In step 2, an augmented CK-PD model for anti-CD19 CAR-Ts was developed, by integrating CK dataset(s) from two bioanalytical measurements (qPCR and flow cytometry) in cancer patients. The model described the differential in vivo expansion properties of CAR-T cell subsets. The estimated expansion rate constant was ~1.12-fold higher for CAR+CD8+ cells in comparison to CAR+CD4+ T cells. In step 3, the model was extended to characterize the disposition of four Immunophenotypic populations of CAR-T cells, including stem-cell memory (T ), central memory (T ), effector memory (T ) and effector (T ) cells. The model adequately characterized the longitudinal changes in immunophenotypes post anti-CD19 CAR-T cell infusion in acute lymphocytic leukemia paediatric patients. Polyclonality in the pre-infusion product was identified as a categorical covariate influencing differentiation of immunophenotypes. In the future, this model could be leveraged a priori towards optimizing the composition of CAR-T cell infusion product, and further understand the CK-PD relationship in patients.