Bench‐to‐bedside translation of chimeric antigen receptor (CAR) T cells using a multiscale systems pharmacokinetic‐pharmacodynamic model: A case study with anti‐BCMA CAR‐T

Abstract

Despite tremendous success of chimeric antigen receptor (CAR) T cell therapy in clinical oncology, the dose-exposure-response relationship of CART cells in patients is poorly understood. Moreover, the key drug-and system-specific determinants leading to favourable clinical outcomes are also unknown. Here, we have developed a multiscale mechanistic PK-PD model for anti-BCMA (bb2121) CART cell therapy to characterize 1) in vitro target cell killing in multiple BCMA expressing tumor cell lines at varying E:T ratios, 2) preclinical in vivo tumor growth inhibition (TGI) and blood CART cell expansion in xenograft mice, and 3) clinical PK and PD biomarkers in multiple myeloma (MM) patients. Our translational PK-PD relationship was able to effectively describe the commonly observed multiphasic CART cell PK profile in clinic, consisting of rapid distribution, expansion, contraction and persistent phases, as well as 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 CART cell functionality and suggested that patient baseline tumor burden could be more sensitive than dose levels towards overall extent of exposure (Cmax) after CART cell infusion. Virtual patient simulations also suggested a very steep dose-exposure-response relationship with CART cell therapy and indicated presence of a 'threshold' dose, beyond which a flat dose-response curve could be observed. Our simulations were concordant with multiple clinical observations discussed within this paper. Moving forward, this framework could be leveraged a priori, to explore multiple infusions and support preclinical/clinical development of future CART cell therapies.

Dose-dependent thresholds of dexamethasone destabilize CAR T-cell treatment efficacy

“…Generally, the Holling Type II and III interactions are used to model changes in cell-cell interactions, notably predator-prey handling time and density-dependent behavior. Additionally, where the CARRGO model combines CAR T-cell proliferation and exhaustion into one parameter, κ 2 , other approaches may incorporate a second T-cell type altogether [ 20 , 45 ], a population of macrophages [ 44 ], or explicitly accounting for the pharmacodynamic and pharmacokinetics of CAR T-cell dynamics [ 47 ]. Interestingly, recent theoretical work has shown that a two T-cell type predator-prey model with Holling Type I interactions can, in the appropriate limits and conditions, reduce to a single T-cell type predator-prey model with a Holling Type II interaction [ 43 ].…”

Development of minimal physiologically-based pharmacokinetic-pharmacodynamic models for characterizing cellular kinetics of CAR T cells following local deliveries in mice

“…Our modeling effort revealed the importance of characterizing CAR T cells fitness over the study duration, for example, using kinetic immunophenotyping, to better understand the cellular kinetics and the duration of response. Emerging efforts in quantitative characterization different phenotypes of CAR T cells have been reported in the literature [ 7 , 28 , 29 ].…”

Quantification of cell-free DNA for the analysis of CD19-CAR-T cells during lymphoma treatment

“…CAR-T cell expansion and persistence are major factors in CAR-T cell treatment, but treatment response is dependent on multiple factors, explaining incongruent results between CAR-T cell kinetics and treatment response. 33 To further understand the kinetics of cfDNA in cellular immunotherapy, simultaneous investigation of CAR-T and lymphoma-derived cfDNA during treatment will be of interest in future studies. 34 Particularly, cfDNA analysis is attractive to investigate both lymphoma-derived DNA and cfCAR-DNA, as it contains DNA fragments from all areas of the body.…”