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Published on: October 20, 2016
Effects of CCN1 and Macrophage Content on Glioma Virotherapy: A Mathematical Model
Karly Jacobsen1, Luke Russell, Balveen Kaur
1Mathematical Biosciences Institute, The Ohio State University, Columbus, OH, 43210, USA, jacobsen.50@mbi.osu.edu.
Abstract:
Oncolytic virus (OV) is a genetically engineered virus that can selectively replicate in and kill tumor cells while not harming normal cells. OV therapy has been explored as a treatment for numerous cancers including glioblastoma, an aggressive and devastating brain tumor. Experiments show that extracellular matrix protein CCN1 limits OV therapy of glioma by orchestrating an antiviral response and enhancing the proinflammatory activation and migration of macrophages. Neutralizing CCN1 by antibody has been demonstrated to improve OV spread and tends to increase the time to disease progression. In this paper, we develop a mathematical model to investigate the effects of CCN1 on the treatment of glioma with oncolytic herpes simplex virus. We show that numerical simulations of the model are in agreement with the experimental results and then use the model to explore the anti-tumor effects of combining antibodies with OV therapy. Model simulations suggest that the macrophage content of the tumor is a critical factor to the success of OV therapy and to the reduction in tumor volume gained with the CCN1 antibody.
Insights
Extracellular matrix protein CCN1 hinders oncolytic virus (OV) therapy for glioma. Neutralizing CCN1 with antibodies improves OV spread and tumor reduction, particularly in macrophage-rich tumors.
Area of Science:
- Oncology
- Virology
- Immunology
- Computational Biology
Background:
- Oncolytic virus (OV) therapy shows promise for glioblastoma treatment.
- Extracellular matrix protein CCN1 impedes OV efficacy by promoting antiviral responses and macrophage activation.
- Antibody-mediated neutralization of CCN1 enhances OV spread and delays disease progression in preclinical models.
Purpose of the Study:
- To investigate the impact of CCN1 on oncolytic herpes simplex virus therapy for glioma using a mathematical model.
- To explore the synergistic anti-tumor effects of combining CCN1-neutralizing antibodies with OV therapy.
Main Methods:
- Development of a mathematical model simulating glioma treatment with OV.
- Numerical simulations to analyze the influence of CCN1 and macrophage content on OV therapy outcomes.
- Comparison of model predictions with experimental findings.
Main Results:
- Model simulations align with experimental data, confirming CCN1's inhibitory role in OV therapy.
- Simulations indicate that CCN1 neutralization enhances OV spread and anti-tumor effects.
- Tumor macrophage content is identified as a critical factor for successful OV therapy and antibody combination treatment.
Conclusions:
- CCN1 neutralization is a potential strategy to improve oncolytic virus therapy for glioma.
- Mathematical modeling provides valuable insights into the complex interactions governing OV therapy efficacy.
- Targeting CCN1 in combination with OV therapy, especially in tumors with high macrophage infiltration, may enhance treatment outcomes.
