Quantitative Mechanistic Modeling in Support of Pharmacological Therapeutics Development in Immuno-Oncology.

Following the approval, in recent years, of the first immune checkpoint inhibitor, there has been an explosion in the development of immuno-modulating pharmacological modalities for the treatment of various cancers. From the discovery phase to late-stage clinical testing and regulatory approval, challenges in the development of immuno-oncology (IO) drugs are multi-fold and complex. In the preclinical setting, the multiplicity of potential drug targets around immune checkpoints, the growing list of immuno-modulatory molecular and cellular forces in the tumor microenvironment-with additional opportunities for IO drug targets, the emergence of exploratory biomarkers, and the unleashed potential of modality combinations all have necessitated the development of quantitative, mechanistically-oriented systems models which incorporate key biology and patho-physiology aspects of immuno-oncology and the pharmacokinetics of IO-modulating agents. In the clinical setting, the qualification of surrogate biomarkers predictive of IO treatment efficacy or outcome, and the corresponding optimization of IO trial design have become major challenges. This mini-review focuses on the evolution and state-of-the-art of quantitative systems models describing the tumor vs. immune system interplay, and their merging with quantitative pharmacology models of IO-modulating agents, as companion tools to support the addressing of these challenges.