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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 T‐cells against CD19+ cell lines at varying effector:target ratios. In step 2, an augmented CK‐PD model for anti‐CD19 CAR T‐cells was developed, by integrating CK dataset(s) from two bioanalytical measurements (quantitative polymerase chain reaction and flow cytometry) in patients with cancer. 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, central memory, effector memory, and effector cells. The model adequately characterized the longitudinal changes in immunophenotypes post anti‐CD19 CAR T‐cell infusion in pediatric patients with acute lymphocytic leukemia. 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 toward optimizing the composition of CAR T‐cell infusion product, and further understand the CK‐PD relationship in patients.

Abstract Despite tremendous success of chimeric antigen receptor (CAR) T cell therapy in clinical oncology, the dose‐exposure‐response relationship of CAR‐T cells in patients is poorly understood. Moreover, the key drug‐specific and system‐specific determinants leading to favorable clinical outcomes are also unknown. Here we have developed a multiscale mechanistic pharmacokinetic (PK)‐pharmacodynamic (PD) model for anti‐B‐cell maturation antigen (BCMA) CAR‐T cell therapy (bb2121) to characterize (i) in vitro target cell killing in multiple BCMA expressing tumor cell lines at varying effector to target cell ratios, (ii) preclinical in vivo tumor growth inhibition and blood CAR‐T cell expansion in xenograft mice, and (iii) clinical PK and PD biomarkers in patients with multiple myeloma. Our translational PK‐PD relationship was able to effectively describe the commonly observed multiphasic CAR‐T cell PK profile in the clinic, consisting of the rapid distribution, expansion, contraction, and persistent phases, and accounted for the categorical individual responses in multiple myeloma to effectively calculate progression‐free survival rates. Preclinical and clinical data analysis revealed comparable parameter estimates pertaining to CAR‐T cell functionality and suggested that patient baseline tumor burden could be more sensitive than dose levels toward overall extent of exposure after CAR‐T cell infusion. Virtual patient simulations also suggested a very steep dose‐exposure‐response relationship with CAR‐T cell therapy and indicated the presence of a “threshold” dose, beyond which a flat dose‐response curve could be observed. Our simulations were concordant with multiple clinical observations discussed in this article. Moving forward, this framework could be leveraged a priori to explore multiple infusions and support the preclinical/clinical development of future CAR‐T cell therapies.