Development of a quantitative relationship between CAR-affinity, antigen abundance, tumor cell depletion and CAR-T cell expansion using a multiscale systems PK-PD model

MAbs. 2020 Jan-Dec;12(1):1688616. doi: 10.1080/19420862.2019.1688616.


The development of mechanism-based, multiscale pharmacokinetic-pharmacodynamic (PK-PD) models for chimeric antigen receptor (CAR)-T cells is needed to enable investigation of in vitro and in vivo correlation of CAR-T cell responses and to facilitate preclinical-to-clinical translation. Toward this goal, we first developed a cell-level in vitro PD model that quantitatively characterized CAR-T cell-induced target cell depletion, CAR-T cell expansion and cytokine release. The model accounted for key drug-specific (CAR-affinity, CAR-densities) and system-specific (antigen densities, E:T ratios) variables and was able to characterize comprehensive in vitro datasets from multiple affinity variants of anti-EGFR and anti-HER2 CAR-T cells. Next, a physiologically based PK (PBPK) model was developed to simultaneously characterize the biodistribution of untransduced T-cells, anti-EGFR CAR-T and anti-CD19 CAR-T cells in xenograft -mouse models. The proposed model accounted for the engagement of CAR-T cells with tumor cells at the site of action. Finally, an integrated PBPK-PD relationship was established to simultaneously characterize expansion of CAR-T cells and tumor growth inhibition (TGI) in xenograft mouse model, using datasets from anti-BCMA, anti-HER2, anti-CD19 and anti-EGFR CAR-T cells. Model simulations provided potential mechanistic insights toward the commonly observed multiphasic PK profile (i.e., rapid distribution, expansion, contraction and persistence) of CAR-T cells in the clinic. Model simulations suggested that CAR-T cells may have a steep dose-exposure relationship, and the apparent Cmax upon CAR-T cell expansion in blood may be more sensitive to patient tumor-burden than CAR-T dose levels. Global sensitivity analysis described the effect of other drug-specific parameters toward CAR-T cell expansion and TGI. The proposed modeling framework will be further examined with the clinical PK and PD data, and the learnings can be used to inform design and development of future CAR-T therapies.

Keywords: Physiologically-based pharmacokinetic models; cell-level models; chimeric Antigen receptor T cells; cytokine release; global sensitivity analysis; immuno-oncology; tumor growth inhibition (TGI).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Movement
  • Cell Proliferation
  • Computer Simulation
  • ErbB Receptors / immunology
  • Heterografts
  • Humans
  • Immunotherapy, Adoptive / methods*
  • Mice
  • Models, Theoretical
  • Neoplasms / immunology*
  • Neoplasms / therapy
  • Protein Binding
  • Receptor, ErbB-2 / immunology
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / immunology
  • Receptors, Chimeric Antigen / metabolism*
  • T-Lymphocytes / immunology*


  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen
  • EGFR protein, human
  • ERBB2 protein, human
  • ErbB Receptors
  • Receptor, ErbB-2

Grants and funding

This work was supported by the Janssen Biotherapeutics, Janssen Research and Development, The Pharmaceutical Company of Johnson and Johnson.