Cellular kinetics: A clinical and computational review of CAR-T cell pharmacology

Timothy Qi; Kyle McGrath; Raghuveer Ranganathan; Gianpietro Dotti; Yanguang Cao

doi:10.1016/j.addr.2022.114421

Cellular kinetics: A clinical and computational review of CAR-T cell pharmacology

Adv Drug Deliv Rev. 2022 Sep:188:114421. doi: 10.1016/j.addr.2022.114421. Epub 2022 Jul 6.

Authors

Timothy Qi¹, Kyle McGrath², Raghuveer Ranganathan³, Gianpietro Dotti⁴, Yanguang Cao⁵

Affiliations

¹ Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; University of Florida College of Medicine, The University of Florida, Gainesville, FL 32610, USA.
³ Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Kenneth Norris Jr. Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA.
⁴ Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. Electronic address: gianpi@email.unc.edu.
⁵ Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: yanguang@unc.edu.

Abstract

To the extent that pharmacokinetics influence the effectiveness of nonliving therapeutics, so too do cellular kinetics influence the efficacy of Chimeric Antigen Receptor (CAR) -T cell therapy. Like conventional therapeutics, CAR-T cell therapies undergo a distribution phase upon administration. Unlike other therapeutics, however, this distribution phase is followed by subsequent phases of expansion, contraction, and persistence. The magnitude and duration of these phases unequivocally influence clinical outcomes. Furthermore, the "pharmacodynamics" of CAR-T cells is truly dynamic, as cells can rapidly become exhausted and lose their therapeutic efficacy. Mathematical models are among the translational tools commonly applied to assess, characterize, and predict the complex cellular kinetics and dynamics of CAR-T cells. Here, we provide a focused review of the cellular kinetics of CAR-T cells, the mechanisms underpinning their complexity, and the mathematical modeling approaches used to interrogate them.

Keywords: CAR-T cells; Cancer immunology; Immunotherapy; Lymphocyte trafficking; Mathematical modeling; Translational science.

Publication types

Review
Research Support, N.I.H., Extramural

MeSH terms

Humans
Immunotherapy, Adoptive
Kinetics
Receptors, Chimeric Antigen*
T-Lymphocytes*

Substances

Receptors, Chimeric Antigen

Abstract

Publication types

MeSH terms

Substances

Grants and funding