Abstract
Oncolytic virotherapies, including the modified herpes simplex virus talimogene laherparepvec (T-VEC), have shown great promise as potent instigators of anti-tumour immune effects. The OPTiM trial, in particular, demonstrated the superior anti-cancer effects of T-VEC as compared to systemic immunotherapy treatment using exogenous administration of granulocyte-macrophage colony-stimulating factor (GM-CSF). Theoretically, a combined approach leveraging exogenous cytokine immunotherapy and oncolytic virotherapy would elicit an even greater immune response and improve patient outcomes. However, regimen scheduling of combination immunostimulation and T-VEC therapy has yet to be established. Here, we calibrate a computational biology model of sensitive and resistant tumour cells and immune interactions for implementation into an in silico clinical trial to test and individualize combination immuno- and virotherapy. By personalizing and optimizing combination oncolytic virotherapy and immunostimulatory therapy, we show improved simulated patient outcomes for individuals with late-stage melanoma. More crucially, through evaluation of individualized regimens, we identified determinants of combination GM-CSF and T-VEC therapy that can be translated into clinically-actionable dosing strategies without further personalization. Our results serve as a proof-of-concept for interdisciplinary approaches to determining combination therapy, and suggest promising avenues of investigation towards tailored combination immunotherapy/oncolytic virotherapy.
Highlights
Modern cancer treatments increasingly incorporate a broad class of biological therapies known as immunotherapies to activate the immune system against cancer cells in a generalized or targeted way [1, 2]
The advent of biological therapies for anti-cancer treatment has had a significant impact on patient outcomes
To establish the synergistic interactions elicited between immunotherapy and oncolytic virotherapy, we adapted our previous mathematical model [28] describing the instantaneous change in tumour size, phagocyte numbers and cytokine concentrations over time
Summary
Modern cancer treatments increasingly incorporate a broad class of biological therapies known as immunotherapies to activate the immune system against cancer cells in a generalized or targeted way [1, 2]. GM-CSF has been used to increase the efficacy of monoclonal antibodies, and has been administered during B-cell lymphoma treatment to activate certain immune cell subsets [2] Another older idea, recently adopted in clinical applications, is to use oncolytic viruses to destroy tumour cells [3, 4] and activate an immune response. Oncolytic viruses are genetically engineered to preferentially attack and infect cancerous cells [5, 6], forcing infected cells to undergo lysis and release tumour specific antigens that signal the immune system to mount an anti-tumour response [7, 8]. GM-CSF has been considered as an immune stimulant during oncolytic virotherapy [2]
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