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 218 patients from 7 trials and systematically compared CAR-T kinetics across patient populations and tumor types. Based on our analysis results, CAR-T cells exhibited a significantly higher cell proliferation rate constant and capacity but a lower contraction rate constant in patients who responded to treatment. CAR-T cells proliferate at a higher rate constant 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, suggesting steep dose-response curves. In conclusion, the developed CAR-T cellular kinetic model adequately characterized the multiphasic CAR-T cellular kinetics and supported systematic evaluations of the potentially influencing factors, which can have significant implications for the development of more effective CAR-T therapies.

In Vivo Cellular Expansion of Lisocabtagene Maraleucel and Association With Efficacy and Safety in Relapsed/Refractory Large B‐Cell Lymphoma

“…Although the JULIET trial (tisagenlecleucel) 13 sample size was smaller and enrollment criteria were not identical to TRANSCEND, there were also sample size and enrollment criteria differences between the ZUMA‐1 trial (axicabtagene ciloleucel) 16 and TRANSCEND, yet an association between higher expansion and response was observed in both of these LBCL studies. Higher in vivo CAR T‐cell expansion in responders has also been observed for non–CD19‐directed CAR T‐cell therapy in other indications (multiple myeloma and non–small cell lung cancer) 18,19 . TRANSCEND is the largest clinical study reported to date of CD19‐directed CAR T‐cell therapy in R/R LBCL 7,10,16,20,21 .…”

“…Higher in vivo CAR T-cell expansion in responders has also been observed for non-CD19-directed CAR T-cell therapy in other indications (multiple myeloma and non-small cell lung cancer). 18,19 TRANSCEND is the largest clinical study reported to date of CD19-directed CAR T-cell therapy in R/R LBCL. 7,10,16,20,21 This article, to the best of our knowledge, describes for the first time the relationship between in vivo cellular expansion and efficacy or safety of CAR T-cell therapy controlling for potentially confounding baseline factors.…”

Pharmacokinetic—Pharmacodynamic Modeling of Tumor Targeted Drug Delivery Using Nano-Engineered Mesenchymal Stem Cells

“…Numerous mechanistic PK–PD models have been developed over the last decade for therapies using small molecule compounds, monoclonal antibodies and antibody drug conjugates [ 24 , 25 , 26 ]. However, very few studies have focused on modeling cell-based therapies [ 27 , 28 ].…”

A computational model of CAR T-cell immunotherapy predicts leukemia patient responses at remission, resistance, and relapse

“…Other approaches focus mostly on modeling factors underlying CAR T-cell dynamics, such as ecological dynamics regulated CAR T-cell explain expansion ( 9 ) and exhaustion ( 10 ), signaling-induced cell state variability ( 11 ), and CAR T-cell expansion due to lymphodepletion and competitive growth between CAR T-cell and normal T-cell ( 12 ). Lately, Liu et al developed a model to characterize clinical CAR T-cell kinetics across response status, patient populations, and tumor types, yet only in a retrospective manner ( 13 ). However, these computational models typically fail to provide a collective analysis and effective interpretation of clinical trial data from different clinical studies to reveal the key cellular mechanisms underlying the heterogeneous patient outcomes observed in different clinical trials.…”

“…Day -1 0.069 0.080 0.21 0.071 (45,46) rTA Growth rate of activated CAR T-cell Day -1 1.62 0.99 0.99 1.5 (13,47) lTA Apoptosis rate of activated CAR T-cell Day -1 0.12 0.55 0.12 0.11 (48,49) lTN…”