A Multiple-Model-Informed Drug-Development Approach for Optimal Regimen Selection of an Oncolytic Virus in Combination With Pembrolizumab.

The antitumor efficacy of an intratumoral injection of a genetically engineered oncolytic vaccinia virus carrying human IL-7 and murine IL-12 genes (hIL-7/mIL-12-VV) was demonstrated in CT26.WT-bearing mice. In the CT26.WT-bearing mouse model, the efficacy of the combination of hIL-7/mIL-12-VV plus the anti-programmed cell death protein (PD)-1 antibody was determined to be correlated with the timing of administration: greater efficacy was observed when hIL-7/mIL-12-VV was administered before the anti-PD-1 agent instead of simultaneous administration. To identify an optimal dosing regimen for first-in-human clinical trials, a multiple model-informed drug-development (MIDD) approach was used through development of a quantitative systems pharmacology (QSP) model and an agent-based model (ABM). All models were built and verified using available literature and preclinical study data. Multiple dosing scenarios were explored using virtual populations by altering the interval between hIL-7/hIL-12-VV and pembrolizumab administration. In contrast with observations from preclinical studies, both the QSP and the ABM models demonstrated no antagonistic effect on the dose-dependent antitumor efficacy of hIL-7/hIL-12-VV by pembrolizumab in simulations of clinical therapy. Based on the MIDD strategy, it was recommended that the highest dose of hIL-7/hIL-12-VV and pembrolizumab should be administered on the same day, but with pembrolizumab administration following hIL-7/hIL-12-VV administration. Multiple different modeling approaches uniquely supported and informed the first-in-human clinical trial design by guiding the optimal dose and regimen selection.