Quantitative Systems Pharmacology Modeling in Immuno-Oncology: Hypothesis Testing, Dose Optimization, and Efficacy Prediction.

Abstract

Despite an increasing number of clinical trials, cancer is one of the leading causes of death worldwide in the past decade. Among all complex diseases, clinical trials in oncology have among the lowest success rates, in part due to the high intra- and inter-tumoral heterogeneity. There are more than a thousand cancer drugs and treatment combinations being investigated in ongoing clinical trials for various cancer subtypes, germline mutations, metastasis, etc. Particularly, treatments relying on the (re)activation of the immune system have become increasingly present in the clinical trial pipeline. However, the complexities of the immune response and cancer-immune interactions pose a challenge to the development of these therapies. Quantitative systems pharmacology (QSP), as a computational approach to predict tumor response to treatments of interest, can be used to conduct in silico clinical trials with virtual patients (and emergent use of digital twins) in place of real patients, thus lowering the time and cost of clinical trials. In line with improved mechanistic understanding of the human immune system and promising results from recent cancer immunotherapy, QSP models can play critical roles in model-informed drug development in immuno-oncology. In this chapter, we discuss how QSP models were designed to serve different study objectives, including hypothesis testing, dose optimization, and efficacy prediction, via case studies in immuno-oncology.