Abstract 265: Evaluating variation in drug efficacy endpoints in a syngeneic mouse model (CT26.WT) under immune checkpoint blockade

Abstract

Abstract INTRODUCTION: Preclinical research into immune checkpoint blockade (ICB) requires in vivo models with fully functional immunity. Syngeneic mouse models are homografts derived by transplanting immortalized mouse cancer cell lines or tumor tissues into strain-matched mouse hosts, and are well suited for evaluating the efficacy of new immunotherapies due to retaining an intact mouse immune system. Tumor growth inhibition (TGI) is widely used to characterize drug efficacy, however, a considerable amount of heterogeneity among TGI is often observed for a given ICB treatment in the same syngeneic mouse model. It is of vital importance to understand the source of such variation. The present study sets out to systematically investigate the variation of TGI for ICB treatment in syngeneic mouse models, using tumor growth data of anti-PD-1 treatment in the CT26.WT syngeneic mouse model for 27 independent studies. METHODS: For each study, we calculated TGI and median area under curve (AUC) ratio on the corresponding study day when tumor volume data was collected. We utilized standard deviation and inter quantile range to quantify the variation. We evaluated the relationship between TGI and the corresponding day, and also compared the variation between TGI and median AUC ratio. Furthermore, to better understand the source of drug efficacy variation, we utilized a Bayesian multilevel model to quantify the amount of tumor growth variation at both the study and mouse level. RESULTS: We found that TGI variation was much higher at earlier stages of studies. In contrast, the median AUC ratio showed smaller variation across the duration of each study than TGI for the majority of studies. Additionally, we found neither TGI nor median AUC ratio had significant correlation with the number of mice used in the study. Based on a Bayesian multilevel model, we observed that drug efficacy had larger variation on the mouse level (i.e. within a study), than variation on the study level (i.e. observed between studies), which could indicate heterogeneity of the tumor microenvironment (e.g. TILs) among mice play a major role in the variation of ICB treatment efficacy among studies. CONCLUSIONS: Response to ICB treatment among mice of the same syngeneic model is inherently heterogeneous. TGI of later time points should be favored to reduce variation, and generally median AUC Ratio is more stable than TGI. Citation Format: Binchen Mao, Sheng Guo, Davy Ouyang, Henry Li. Evaluating variation in drug efficacy endpoints in a syngeneic mouse model (CT26.WT) under immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 265.