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

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.

Conducting a Virtual Clinical Trial in HER2-Negative Breast Cancer Using a Quantitative Systems Pharmacology Model With an Epigenetic Modulator and Immune Checkpoint Inhibitors

“…Notably, the predictions of anti-tumor response and predictive biomarkers are strongly affected by our assumptions on mechanism of action for all therapeutics and distribution of physiological parameters for virtual patient cohort (Cassidy and Craig, 2019). The expected response rate of the ongoing clinical trial simulated in this study, as suggested by the 95% percentile bootstrap confidence intervals, could fall into a wide range.…”

PI3K inhibitor significantly enhances the antitumor activity of oncolytic virus in osteosarcoma

“…The main focus of oncolytic virus therapy is to directly kill the tumor cells as well as activate the anti-tumor immune response [28]. Genetically engineered recombinant oncolytic viruses have also been designed in order to improve antitumor activity [29]. However, this strategy is limited by the small viral genomes and technical di culty.…”

Optimising Hydrogel Release Profiles for Viro-Immunotherapy Using Oncolytic Adenovirus Expressing IL-12 and GM-CSF with Immature Dendritic Cells

“…Genetic algorithms are heuristic global optimisation routines inspired by natural selection that are frequently employed to estimate parameters in computational biology models. They have previously been applied to study optimal dosing routines in immunology [54,55] and combined oncolytic virotherapy and immunotherapy [29].…”

“…Deterministic systems of ordinary differential equations (ODEs) are used to describe the key biophysical interactions and are then analysed to determine optimal therapeutic protocols [23]. In oncology, these techniques have been used to successfully optimise chemotherapy and immunotherapy treatment [25][26][27][28][29][30]. Zhu et al [31] optimised the scheduling of one cycle of chemotherapy drug VP-16 and found a new optimal drug regime which improved the clinical efficacy.…”

“…Optimising the scheduling of systemic doses of DCs and oncolytic virus, Wares et al [37] found that tumour eradication could be achieved only when oncolytic viruses were administered before DCs. In work by Cassidy and Craig [29], an optimised schedule for combined virotherapy and chemotherapy treatment was obtained using a genetic algorithm. So far, however, no one has optimised the release profile of viro-immunotherapy from a sustained-delivery system.…”