Population Cellular Kinetics of Lisocabtagene Maraleucel, an Autologous CD19-Directed Chimeric Antigen Receptor T-Cell Product, in Patients with Relapsed/Refractory Large B-Cell Lymphoma

• Published in: Clinical pharmacokinetics Vol. 60; no. 12; pp. 1621 - 1633
• Main Authors: Ogasawara, Ken, Dodds, Michael, Mack, Timothy, Lymp, James, Dell’Aringa, Justine, Smith, Jeff
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2021; Springer Nature B.V
• Subjects: Antigens; Antigens, CD19; Chemotherapy; Genomes; Humans; Internal Medicine; Kinetics; Lymphocytes; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Medicine; Medicine & Public Health; NCT; NCT02631044; Original; Original Research Article; Patients; Pharmacology/Toxicology; Pharmacotherapy; Polymerase chain reaction; Population; Receptors, Antigen, T-Cell - genetics; Receptors, Chimeric Antigen - genetics; T-Lymphocytes
• ISSN: 0312-5963; 1179-1926; 1179-1926
• DOI: 10.1007/s40262-021-01039-5

Background and Objectives Lisocabtagene maraleucel (liso-cel) is a CD19-directed, defined composition, 4-1BB chimeric antigen receptor (CAR) T-cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. Large between-subject variability has been noted with CAR T-cell therapies; patient characteristics might contribute to CAR T-cell expansion variability. We developed a population cellular kinetic model to characterize the kinetics of the liso-cel transgene, via quantitative polymerase chain reaction assessment after intravenous infusion of liso-cel, and to understand covariates that might influence liso-cel kinetics in individual patients. Methods We employed nonlinear mixed-effects modeling to develop a population cellular kinetic model for liso-cel. The population cellular kinetic analysis was performed using 2524 post-infusion transgene observations from 261 patients with relapsed/refractory large B-cell lymphoma who were treated with a single dose of liso-cel in TRANSCEND NHL 001. Covariates for the analysis included baseline intrinsic factors such as age, baseline disease characteristics, and liso-cel and coadministration factors. Results Liso-cel cellular kinetics were well described by a piecewise model of cellular growth kinetics that featured lag, exponential growth, and biexponential decay phases. Population means (95% confidence interval) of lag phase duration, doubling time, time to maximum levels, initial decline half-life, and terminal half-life were 3.27 (2.71–3.97), 0.755 (0.667–0.821), 9.29 (8.81–9.70), 5.00 (4.15–5.90), and 352 (241–647) days, respectively. The magnitude of effect on liso-cel expansion metrics demonstrated that the covariate associations were smaller than the residual between-subject variability in the population. Conclusions The covariates tested were not considered to have a meaningful impact on liso-cel kinetics. Clinical Trial Registration NCT02631044.