Determinants of combination GM-CSF immunotherapy and oncolytic virotherapy success identified through in silico treatment personalization

摘要

The advent of biological therapies for anti-cancer treatment has had a significant impact on patient outcomes. Targeted xenobiotics, including oncolytic viruses, in combination with existing, more general, immunotherapies like exogenous cytokines show great promise for continuing to improve cancer care. However, determining optimal combination regimens can be difficult, given that testing proposed schedules would require large cohorts of patients enrolled in clinical trials. Fortunately, computational biology can help to address treatment scheduling while simultaneously helping to unravel the mechanisms driving therapeutic responses. In this work, we integrate a mathematical model of GM-CSF and talimogene laherparepvec (T-VEC) oncolytic virotherapy into a virtual clinical trial to optimize their administration in combination. Using this platform, we inferred a clinically-actionable combination schedule for patients with late-stage melanoma that significantly improved virtual patient outcome when compared to GM-CSF and T-VEC monotherapies, and a standard combination strategy. Our results outline a rational approach to therapy optimization with meaningful consequences for how we effectively design and implement clinical trials to maximize their success, and how we treat melanoma with combined immuno- and virotherapy.