An Agent-Based Model of Combination Oncolytic Viral Therapy and Anti-PD-1 Immunotherapy Reveals the Importance of Spatial Location When Treating Glioblastoma.

Kathleen M Storey,Trachette L Jackson

doi:10.3390/cancers13215314

Kathleen M Storey, Trachette L Jackson

Open Access

https://doi.org/10.3390/cancers13215314

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Journal: Cancers	Publication Date: Oct 22, 2021
Citations: 13	License type: CC BY 4.0

Affiliation: Lafayette College, University of Michigan–Ann Arbor

Abstract

Oncolytic viral therapies and immunotherapies are of growing clinical interest due to their selectivity for tumor cells over healthy cells and their immunostimulatory properties. These treatment modalities provide promising alternatives to the standard of care, particularly for cancers with poor prognoses, such as the lethal brain tumor glioblastoma (GBM). However, uncertainty remains regarding optimal dosing strategies, including how the spatial location of viral doses impacts therapeutic efficacy and tumor landscape characteristics that are most conducive to producing an effective immune response. We develop a three-dimensional agent-based model (ABM) of GBM undergoing treatment with a combination of an oncolytic Herpes Simplex Virus and an anti-PD-1 immunotherapy. We use a mechanistic approach to model the interactions between distinct populations of immune cells, incorporating both innate and adaptive immune responses to oncolytic viral therapy and including a mechanism of adaptive immune suppression via the PD-1/PD-L1 checkpoint pathway. We utilize the spatially explicit nature of the ABM to determine optimal viral dosing in both the temporal and spatial contexts. After proposing an adaptive viral dosing strategy that chooses to dose sites at the location of highest tumor cell density, we find that, in most cases, this adaptive strategy produces a more effective treatment outcome than repeatedly dosing in the center of the tumor.

Highlights

Glioblastoma (GBM) is the most aggressive form of brain tumor, and its poor average survival rate of 1–2 years has remained largely constant for many years, despite significant advancements in other cancer treatment modalities [1]
We investigate the impact of the tumor cell killing rate, kTA, by antitumor T cells on the tumor response to treatment
We developed an agent-based model (ABM) to model the response of GBM to a combination of oncolytic viral therapy and anti-PD-1 immunotherapy

Summary

Introduction

Glioblastoma (GBM) is the most aggressive form of brain tumor, and its poor average survival rate of 1–2 years has remained largely constant for many years, despite significant advancements in other cancer treatment modalities [1]. Due to oncolytic viruses’ ability to selectively target tumor cells over healthy cells, OVT has the potential to perform better than the standard GBM treatment protocol when it is combined with an anti-PD-1 immunotherapy, a treatment that targets the protein PD-1, primarily found on T cells. This treatment blocks the immune checkpoint formed when PD-1 binds to PD-L1, which is upregulated on cancer cells. Combining OVT with anti-PD-1 immunotherapy enables a robust immune response to treatment, which aids in targeting tumor cells

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