PT  - JOURNAL ARTICLE
AU  - Adrianne L Jenner
AU  - Tyler Cassidy
AU  - Katia Belaid
AU  - Marie-Claude Bourgeois-Daigneault
AU  - Morgan Craig
TI  - In silico trials predict that combination strategies for enhancing vesicular stomatitis oncolytic virus are determined by tumor aggressivity
AID  - 10.1136/jitc-2020-001387
DP  - 2021 Feb 01
TA  - Journal for ImmunoTherapy of Cancer
PG  - e001387
VI  - 9
IP  - 2
4099  - http://jitc.bmj.com/content/9/2/e001387.short
4100  - http://jitc.bmj.com/content/9/2/e001387.full
SO  - J Immunother Cancer2021 Feb 01; 9
AB  - Background Immunotherapies, driven by immune-mediated antitumorigenicity, offer the potential for significant improvements to the treatment of multiple cancer types. Identifying therapeutic strategies that bolster antitumor immunity while limiting immune suppression is critical to selecting treatment combinations and schedules that offer durable therapeutic benefits. Combination oncolytic virus (OV) therapy, wherein complementary OVs are administered in succession, offer such promise, yet their translation from preclinical studies to clinical implementation is a major challenge. Overcoming this obstacle requires answering fundamental questions about how to effectively design and tailor schedules to provide the most benefit to patients.Methods We developed a computational biology model of combined oncolytic vaccinia (an enhancer virus) and vesicular stomatitis virus (VSV) calibrated to and validated against multiple data sources. We then optimized protocols in a cohort of heterogeneous virtual individuals by leveraging this model and our previously established in silico clinical trial platform.Results Enhancer multiplicity was shown to have little to no impact on the average response to therapy. However, the duration of the VSV injection lag was found to be determinant for survival outcomes. Importantly, through treatment individualization, we found that optimal combination schedules are closely linked to tumor aggressivity. We predicted that patients with aggressively growing tumors required a single enhancer followed by a VSV injection 1 day later, whereas a small subset of patients with the slowest growing tumors needed multiple enhancers followed by a longer VSV delay of 15 days, suggesting that intrinsic tumor growth rates could inform the segregation of patients into clinical trials and ultimately determine patient survival. These results were validated in entirely new cohorts of virtual individuals with aggressive or non-aggressive subtypes.Conclusions Based on our results, improved therapeutic schedules for combinations with enhancer OVs can be studied and implemented. Our results further underline the impact of interdisciplinary approaches to preclinical planning and the importance of computational approaches to drug discovery and development.All Matlab code used for generating the virtual cohort and analysis of the cohort under enhancer injection multiplicity and VSV lag is freely available at the GitHub repository https://github.com/adriannejnner/In-silico-trials-for-combination-strategies-for-enhancing-vesicular-stomatisis-oncolytic-virus. The virtual cohort used for our analyses is also available in the repository. Data are available on reasonable request from the corresponding author (morgan.craig@umontreal.ca).