Semi-mechanistic Platform Model for Checkpoint Inhibitors

Background

Syngeneic mouse models have been widely employed in preclinical discovery of checkpoint inhibitors as they enable study of drug impact on the intact immune system (Lechner, 2013; Murphy, 2015). However, the interpretation of such studies remains challenging partly due to the large variability in individual animal responses to drug treatment.

In this collaboration with Pfizer, we describe the generation of a model platform that captures essential aspects of the pharmacokinetics, cellular and tumor growth effects of murine surrogates of two checkpoint therapeutic antibodies, anti-PD1 and anti-CTLA4, in the CT26 syngeneic tumor model. The model describes individual animal responses with regard to drug exposure, key intra-tumoral cell kinetics and tumor volume changes and provides biologically plausible explanations for the observed differences between good and poor responders to treatment with anti-PD1 or anti-CTLA4.

Results

Despite high predicted target occupancy for good responders, dose-dependent TGI response is predicted; for poor responders, complete response is not achieved at the highest dose (ie. 30 mg/kg) tested.
The sensitivity analysis suggested that for poor responders, most of the parameters that impact the response are immune cell/tumor cell related and not drug related. This indicates that immune cell related barriers have to be overcome in order to achieve good tumor killing response.
With similar baseline level of PD1+CD8+ and CTLA4+CD8+, the TGI response with anti-PD1 overall is much smaller than with anti-CTLA4 in CT26 mouse model.

Anti-CTLA4

Anti-PD1

Model Diagram

Common model structure between anti-CTLA-4 and anti-PD-1 models:

3-compartment model: circulation (central), peripheral and tumor.
Central and peripheral compartments include interactions of drug, target (CTLA-4 or PD-1) and soluble target (sCTLA-4 or sPD-1).
Tumor compartment includes interactions of drug, target, soluble target and endogenous ligand (B7 or PD-L1).
A semi-mechanistic model is used to link target occupancy (TO) in tumor to tumor killing. Specifically, CD8 activation rate and Treg depletion rate are modeled to be proportional to the TO on CD8 and Treg, respectively.

Model Prediction and Future Directions

The current model can inform the design of future experiments:

Measure tumor growth for individual animals prior to dosing since tumor growth rate is the most sensitive parameter.
Select time points for PK and TIL measurement that allow refinement of model parameters and model predictions.

This model can be expanded with additional drug mechanisms in a modular fashion and can be mechanistically translated to human using available clinical biomarker data.

Model predictions