A Predictive Model for Synergistic Oncolytic Virotherapy: Unveiling the Ping-Pong Mechanism and Optimal Timing of Combined Vesicular Stomatitis and Vaccinia Viruses

TL;DR

This paper develops a mathematical model elucidating the synergistic mechanism of combined VSV and VV oncolytic virotherapy, highlighting the ping-pong interaction, optimal timing, and key parameters influencing tumor eradication.

Contribution

It introduces a novel mathematical framework capturing the ping-pong synergy and optimal scheduling in combined VSV and VV oncolytic therapy.

Findings

Complete tumor clearance in ~50 days with combination therapy

11% faster than VV monotherapy

Optimal timing involves immediate VSV followed by delayed VV within 1-19 days

Abstract

We present a mathematical model that describes the synergistic mechanism of combined Vesicular Stomatitis Virus (VSV) and Vaccinia Virus (VV). The model captures the dynamic interplay between tumor cells, viral replication, and the interferon-mediated immune response, revealing a `ping-pong' synergy where VV-infected cells produce B18R protein that neutralizes interferon-$\alpha$, thereby enhancing VSV replication within the tumor. Numerical simulations demonstrate that this combination achieves complete tumor clearance in approximately 50 days, representing an 11\% acceleration compared to VV monotherapy (56 days), while VSV alone fails to eradicate tumors. Through bifurcation analysis, we identify critical thresholds for viral burst size and B18R inhibition, while sensitivity analysis highlights infection rates and burst sizes as the most influential parameters for treatment efficacy. Temporal optimization reveals that therapeutic outcomes are maximized through immediate VSV administration followed by delayed VV injection within a 1-19 day window, offering a strategic approach to overcome the timing and dosing challenges inherent in OVT.