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

Abstract

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.

Opportunities for Quantitative Translational Modeling in Oncology

“…95 A second example of the application of mechanistic modeling to IO is the quantitative modeling of chimeric antigen receptor T cell therapies. 96,97 Agent-based and individual-based simulations are increasingly used for this application, with these simulations being, of course, spatially resolved in their outputs. 98 This does, of course, increase their computational cost.…”

T‐cell receptor repertoire analysis for the diagnosis and treatment of solid tumor: A methodology and clinical applications

“…Since the year 2011, there have been rapid developments in the field of immunotherapy, and a range of immunocheckpoint inhibitors (ICIs) have been approved for a range of metastatic cancers, including malignant melanoma, lung, kidney, and bladder cancers [1][2][3][4][5]. In recent years, the clinical trial results of genetically engineered immune cells, including chimeric antigen receptor T-cell (CAR-T), TCRengineered T-cell (TCR-T), chimeric antigen receptor natural killer cell (CAR-NK) and more, in the treatment of hematological tumors have also been encouraging [6][7][8]. Immunotherapy has nowadays developed into a new and promising therapy in addition to surgery, radiotherapy, chemotherapy, and molecular targeted therapy [9].…”

Model-based Cellular Kinetic Analysis of Chimeric Antigen Receptor-T Cells in Humans

“…The high-dose cohort exhibited a significantly higher proliferation rate (ρ), and higher capacity (Cmax) compared to the low-dose cohort (data not shown). Studies also observed limited CAR-T expansion at a low dose (< 5 x 10 7 ) 37,38 , and no CAR-T expansion at very low doses (< 10 6 ) 39 , indicating a potential threshold of dose to assure rapid CAR-T expansion and a steep dose-response curve for CAR-T therapy 2,35,40 .…”

“…In solid tumors, cancer cells are often spatially restricted 34 , providing poor antigen accessibility to CAR-T cells. CAR-T cells have to extravasate into the tumor bed, migrate toward the tumor cells, contact, and then engage the tumor cells 7,35 . Differences in tissue accessibility and delivery rate for CAR-T cells may account for large variability on proliferation rate constant (ρ) between two solid tumor trials ( Fig 4B).…”

“…The contraction and persistent phases are mathematically exchangeable but with different parameter interpretation in comparison with previous models. Along with the rapid expansion of CAR-T candidates, more mechanistic cellular kinetics and dynamics models are warranted to disentangle the complicated relationships between target engagement, tumor burdens, as well as the dynamic native immune systems 35 .…”