Development of a Multiscale Mechanistic Modelling Framework Integrating Differential Cellular Kinetics of CAR-T Cell Subsets and Immunophenotypes in Cancer Patients.
Ahmed M SalemGanesh M MugunduAman P SinghPublished in: CPT: pharmacometrics & systems pharmacology (2023)
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 SCM ), central memory (T CM ), effector memory (T EM ) and effector (T EFF ) 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.
Keyphrases
- stem cells
- low dose
- ejection fraction
- gene expression
- induced apoptosis
- intensive care unit
- single cell
- flow cytometry
- cell therapy
- prognostic factors
- dendritic cells
- mass spectrometry
- mesenchymal stem cells
- cell proliferation
- working memory
- oxidative stress
- bone marrow
- peripheral blood
- liver failure
- chronic kidney disease
- extracorporeal membrane oxygenation
- current status
- pi k akt