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.
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.