Systems biology models for cancer immunotherapy

Abstract

Cancer is a complex disease that continues to affect millions of people around the world every year. With ever-improving science and technology, several forms of treatment have been introduced within the past century and continue to be developed so as to provide increasing chances of survival and comfort to patients. Particularly, the 21st century has seen the blossoming of immunotherapy methods, which exploit the natural immune system's ability to kill tumor cells. Several varieties of immunotherapy exist in order to use all sorts of immune cells, targeting specific antigens expressed on tumors or blocking checkpoints which inhibit necessary immune responses. Unfortunately, there is no perfect immunotherapy that can provide a safe and effective path to remission for every patient. Traditional clinical experimentation, while providing important insight, remains a costly option in increasing our understanding of immunotherapies against cancer. Systems biology methods provide a unique and effective channel for exploring the complex dynamics involved in tumor micro-environments between cancer cells, native immune cells and administered drugs. Resulting insight may be used to inform drug development leading to safe, effective, and personalized therapeutic routines. In this thesis, we start by providing a general overview of cancer biology starting from the cell, and systems biology. We then detail equations and parameters comprising a particular systems biology model for nivolumab, an anti-PD-1 immune checkpoint inhibitor, informed by ex vivo data extracted from patients suffering from head and neck squamous cell carcinoma. We then present results of an examination of sex differences in regards to patient response to nivolumab monotherapy as well as combination therapy with recombinant IL12. Here, the aforementioned model was used alongside basal immune differences between the sexes from the literature to generate virtual cohorts of male and female patients receiving these treatments. Finally, we conclude with a general summary as well as potential future directions involving a similar systems biology model describing cytokine release syndrome as a side-effect of CAR-T cell therapy.