Model-Based Cellular Kinetic Analysis of Chimeric Antigen Receptor-T Cells in Humans
Can Liu
Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Search for more papers by this authorVivaswath S. Ayyar
Discovery and Translational Research, Biologics Development Sciences, Janssen Biotherapeutics, Spring House, Pennsylvania, USA
Search for more papers by this authorXirong Zheng
Discovery and Translational Research, Biologics Development Sciences, Janssen Biotherapeutics, Spring House, Pennsylvania, USA
Search for more papers by this authorWenbo Chen
Discovery and Translational Research, Biologics Development Sciences, Janssen Biotherapeutics, Spring House, Pennsylvania, USA
Search for more papers by this authorSongmao Zheng
Discovery and Translational Research, Biologics Development Sciences, Janssen Biotherapeutics, Spring House, Pennsylvania, USA
Search for more papers by this authorHardik Mody
Discovery and Translational Research, Biologics Development Sciences, Janssen Biotherapeutics, Spring House, Pennsylvania, USA
Search for more papers by this authorWeirong Wang
Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, Spring House, Pennsylvania, USA
Search for more papers by this authorDonald Heald
Discovery and Translational Research, Biologics Development Sciences, Janssen Biotherapeutics, Spring House, Pennsylvania, USA
Search for more papers by this authorCorresponding Author
Aman P. Singh
Discovery and Translational Research, Biologics Development Sciences, Janssen Biotherapeutics, Spring House, Pennsylvania, USA
Correspondence: Aman P. Singh ([email protected]); Yanguang Cao ([email protected])
Search for more papers by this authorCorresponding Author
Yanguang Cao
Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Correspondence: Aman P. Singh ([email protected]); Yanguang Cao ([email protected])
Search for more papers by this authorCan Liu
Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Search for more papers by this authorVivaswath S. Ayyar
Discovery and Translational Research, Biologics Development Sciences, Janssen Biotherapeutics, Spring House, Pennsylvania, USA
Search for more papers by this authorXirong Zheng
Discovery and Translational Research, Biologics Development Sciences, Janssen Biotherapeutics, Spring House, Pennsylvania, USA
Search for more papers by this authorWenbo Chen
Discovery and Translational Research, Biologics Development Sciences, Janssen Biotherapeutics, Spring House, Pennsylvania, USA
Search for more papers by this authorSongmao Zheng
Discovery and Translational Research, Biologics Development Sciences, Janssen Biotherapeutics, Spring House, Pennsylvania, USA
Search for more papers by this authorHardik Mody
Discovery and Translational Research, Biologics Development Sciences, Janssen Biotherapeutics, Spring House, Pennsylvania, USA
Search for more papers by this authorWeirong Wang
Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, Spring House, Pennsylvania, USA
Search for more papers by this authorDonald Heald
Discovery and Translational Research, Biologics Development Sciences, Janssen Biotherapeutics, Spring House, Pennsylvania, USA
Search for more papers by this authorCorresponding Author
Aman P. Singh
Discovery and Translational Research, Biologics Development Sciences, Janssen Biotherapeutics, Spring House, Pennsylvania, USA
Correspondence: Aman P. Singh ([email protected]); Yanguang Cao ([email protected])
Search for more papers by this authorCorresponding Author
Yanguang Cao
Division of Pharmacotherapy and Experimental Therapeutics, School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Correspondence: Aman P. Singh ([email protected]); Yanguang Cao ([email protected])
Search for more papers by this authorAbstract
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.
Conflicts of Interest
V.S.A., X.Z., W.C., S.Z., H.M., W.W., D.H., and A.P.S. are employees of Janssen Biopharmaceutics. All other authors declared no competing interests for this work.
Supporting Information
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| cpt2040-sup-0001-Material.docxWord document, 10.7 MB | Supplementary Material |
| cpt2040-sup-0002-Supinfo.xlsxapplication/excel, 65.4 KB | Supplementary Material |
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