Development of a multiscale mechanistic modeling framework integrating differential cellular kinetics of CAR T‐cell subsets and immunophenotypes in cancer patients

Abstract

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 (TSCM), central memory (TCM), effector memory (TEM) and effector (TEFF) 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.

Phenotypic comparison and the potential antitumor function of immortalized bone marrow-derived macrophages (iBMDMs)

“…Meanwhile, the quantitative systems pharmacology modeling has realized the accurate prediction of tumor therapy and the evaluation of immunotherapy effects by combining pharmacokinetics, pharmacodynamics and disease progression. The model has greatly improved the research and development efficiency of cellular immunotherapy and combination drugs ( 44 , 45 ). It provides an excellent theoretical basis for the promotion of clinical immunotherapy.…”

Moving the needle for oncology dose optimization: A call for action

“…Such holistic integrative approaches are critically important when approaching the development of novel therapeutic modalities such as multi‐specific biologics and cell therapies, where our survey indeed suggested that dose optimization will be most challenging. We are pleased to note steady progress in this area, with several recent publications across all three ASCPT Journals highlighting advances in translational, quantitative, and clinical pharmacology applications for these emerging anticancer therapeutics 50–55 . As we learn from present and future real‐life examples and continue to refine best practices in oncology dose optimization, we invite our readership and cross‐sector practitioners to submit these advances for timely publication.…”

Moving the Needle for Oncology Dose Optimization: A Call for Action

“…We are pleased to note steady progress in this area, with several recent publications across all three ASCPT journals highlighting advances in translational, quantitative, and clinical pharmacology applications for these emerging anticancer therapeutics. [50][51][52][53][54][55] As we learn from present and future real-life examples and continue to refine best practices in oncology dose optimization, we invite our readership and cross-sector practitioners to submit these advances for timely publication.…”