Model‐Based Cellular Kinetic Analysis of Chimeric Antigen Receptor‐T Cells in Humans

Abstract

Chimeric antigen receptor (CAR)‐T cell therapy has achieved considerable success in treating B‐cell hematologic malignancies. However, the challenges of extending CAR‐T therapy to other tumor types, particularly solid tumors, remain appreciable. There are substantial variabilities in CAR‐T cellular kinetics across CAR‐designs, CAR‐T products, dosing regimens, patient responses, disease types, tumor burdens, and lymphodepletion conditions. As a “living drug,” CAR‐T cellular kinetics typically exhibit four distinct phases: distribution, expansion, contraction, and persistence. The cellular kinetics of CAR‐T may correlate with patient responses, but which factors determine CAR‐T cellular kinetics remain poorly defined. Herein, we developed a cellular kinetic model to retrospectively characterize CAR‐T kinetics in 217 patients from 7 trials and compared CAR‐T kinetics across response status, patient populations, and tumor types. Based on our analysis results, CAR‐T cells exhibited a significantly higher cell proliferation rate and capacity but a lower contraction rate in patients who responded to treatment. CAR‐T cells proliferate to a higher degree in hematologic malignancies than in solid tumors. Within the assessed dose ranges (107‒109 cells), CAR‐T doses were weakly correlated with CAR‐T cellular kinetics and patient response status. In conclusion, the developed CAR‐T cellular kinetic model adequately characterized the multiphasic CAR‐T cellular kinetics and supported systematic evaluations of the potential influencing factors, which can have significant implications for the development of more effective CAR‐T therapies.

Early Survival Prediction Framework in CD19-Specific CAR-T Cell Immunotherapy Using a Quantitative Systems Pharmacology Model

“…Log 10 -transformed CCS using C max values for all CAR-T cells derived from flow cytometry were reasonably correlated with log-transformed CCS using C max values derived from cfDNA qPCR ( r = 0.48, p = 0.037) and the CCS qPCR values were significantly higher in the reference expansion population compared to the low expansion subpopulation (median: 83.7 copies g −1 DNA·mL −1 vs. median: 4.16 copies g −1 DNA·mL −1 , p = 0.014) ( Figure 10 a,b). Furthermore, CCS qPCR values were significantly higher in patients with complete response/partial response vs. patients with progressive disease/no response in previously digitized data [ 41 ] of patients with multiple myeloma [ 43 ] ( p = 0.017) and chronic lymphocytic lymphoma [ 42 ] ( p = 0.0051) ( Figure 10 c,d), further supporting our clinical composite score framework.…”

“…A subsequent sensitivity analysis showed that a ten-fold change of this value had a minor impact on the time of maximum T cell concentration but not on the maximum concentration itself (Supplementary Figure S5), which is in line with previously published data [13]. In addition, our model's ability to describe the observed data well using the imputed doses supports previous findings of CAR-T cell doses not being predictive of expansion or response [3,18,41].…”

“…The CCS qPCR was compared between reference expansion population and low expansion subpopulation using a two-sided Wilcoxon test. Two additional previously digitized datasets [ 41 ], reporting C max (assessed by qPCR) and baseline tumor burden in CLL [ 42 ] and MM [ 43 ] patients, were digitized ( Supplementary Figure S2 ). Next, CCS qPCR were computed and the differences between patients with CR/PR and PD/NR assessed using two-sided Wilcoxon tests.…”

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

“…5,6 CAR-T cells exhibit a very unique clinical PK profile, which is often discerned by the rapid distribution, expansion, contraction, and persistence phases. 7,8 Although mathematical models have been developed recently 9,10 to empirically describe the slopes associated with multiphasic PK profiles for CAR-T cells, they have limited capability toward extrapolation to predict the PK and PD behavior of alternative CAR constructs and dose levels. The cellular kinetic behavior of cell therapies is dependent on several (i) drug-specific attributes, such as CARaffinity, CAR-density, effector cell type (αβ T cell, γδ T cell, natural killer cells), costimulatory domains (CD28, 4-1BB); (ii) system-specific attributes such as disease type, tumor accessibility (solid tumor or heme malignancies), and initial tumor burden; as well as (iii) product-specific attributes such as CD4:CD8 ratios, phenotypic composition, transduction efficiency, in vitro effector doubling time, etc.…”

Speed and Location Both Matter: Antigen Stimulus Dynamics Controls CAR-T Cell Response

“…We further verified our model prediction with clinical data. We surveyed the cellular kinetics of CAR-T cells in seven clinical trial cohorts of cancer patients (five hematological and two solid tumors) and extracted data including maximal proliferation (highest concentration of CAR copies in the blood), proliferation duration (time from injection to peak concentration), and contraction rate (slope of decline following the initial peak) across multiple CAR products and tumor types (37). These trials included 217 patients and 22 of which were from the solid tumor trials.…”