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

PLoS Comput Biol. 2019 Nov 27;15(11):e1007495. doi: 10.1371/journal.pcbi.1007495. eCollection 2019 Nov.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Combined Modality Therapy / methods*
  • Computational Biology / methods*
  • Computer Simulation
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology*
  • Humans
  • Immunotherapy / methods
  • Melanoma / pathology
  • Models, Theoretical
  • Oncolytic Virotherapy / methods
  • Oncolytic Viruses / pathogenicity
  • Precision Medicine / methods
  • Proof of Concept Study

Substances

  • Granulocyte-Macrophage Colony-Stimulating Factor

Grants and funding

TC was supported by a Natural Sciences and Engineering Research Council PGS-D award, and MC received funding from Natural Sciences and Engineering Research Council Discovery Grant no. RGPIN-2018-04546. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.