Targeting stem cells with oncolytic viruses: a mathematical modelling approach

Sana Jahedi; Kamran Kaveh; James Watmough; Sana Jahedi; Kamran Kaveh; James Watmough

doi:10.3934/mbe.2025090

Mathematical Biosciences and Engineering

2025, Volume 22, Issue 9: 2458-2485. doi: 10.3934/mbe.2025090

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Targeting stem cells with oncolytic viruses: a mathematical modelling approach

1.
Department of Mathematics and Statistics, Oakland University, Rochester, MI 48309, USA
2.
Department of Mathematics, University of Maryland, College Park, MD 20742, USA
3.
Therapy Modelling & Design Center, Department of Mathematics, University of Minnesota, Minneapolis, MN 55455, USA
4.
Department of Mathematics and Statistics, University of New Brunswick, Fredericton, NB, Canada

Received: 13 April 2025 Revised: 29 June 2025 Accepted: 08 July 2025 Published: 24 July 2025

Intratumoural epigenetic heterogeneity, which affects the outcome of many cancer treatments, results from stem cell-differentiated cell hierarchy. Cancer stem cells, also known as tumour-initiating cells, are a pluripotent subpopulation of tumour cells capable of creating a tumour clone through self-renewal and differentiation. Oncolytic viral therapy is a category of cancer therapeutics with high specificity in targeting cancer cells while leaving normal cells unharmed. More recently, oncolytic viruses have been developed that target tumour initiating cells with some promising results. The question is what values for virus infectivity and stem cell specificity result in the best clinical outcome. To address this question, we model interactions between uninfected and infected cancer cells, within a stem cell-differentiated cell hierarchy, during oncolytic viral therapy. We calculate the basic reproduction number and use it to constrain the infectivity rates of initiating and differentiated cancer cells. Long-term tumour shrinkage is observable when this constraint is met; otherwise, treatment fails. Our results suggest that stem cell specificity of an oncolytic virus depends both on the average infectivity and mitotic rates of infected cells. There is a positive correlation between the average infectivity rate and stem cell specificity for nonmitotic infected cells: when average infectivity is high, an oncolytic virus with higher stem cell specificity leads to smaller tumours. In contrast, when average infectivity is low, the minimum tumour size is obtained when an oncolytic virus with higher potency targeting differentiated cells is used. For the perfect stem cell targeting regimen, we derive the condition that leads to the minimum tumour size.
- oncolytic virus,
- stem cell specificity,
- cancer stem cell,
- stem cell targeting,
- phenotypic heterogeneity,
- mathematical model,
- treatment strategies,
- virotherapy
Citation: Sana Jahedi, Kamran Kaveh, James Watmough. Targeting stem cells with oncolytic viruses: a mathematical modelling approach[J]. Mathematical Biosciences and Engineering, 2025, 22(9): 2458-2485. doi: 10.3934/mbe.2025090

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Abstract

Intratumoural epigenetic heterogeneity, which affects the outcome of many cancer treatments, results from stem cell-differentiated cell hierarchy. Cancer stem cells, also known as tumour-initiating cells, are a pluripotent subpopulation of tumour cells capable of creating a tumour clone through self-renewal and differentiation. Oncolytic viral therapy is a category of cancer therapeutics with high specificity in targeting cancer cells while leaving normal cells unharmed. More recently, oncolytic viruses have been developed that target tumour initiating cells with some promising results. The question is what values for virus infectivity and stem cell specificity result in the best clinical outcome. To address this question, we model interactions between uninfected and infected cancer cells, within a stem cell-differentiated cell hierarchy, during oncolytic viral therapy. We calculate the basic reproduction number and use it to constrain the infectivity rates of initiating and differentiated cancer cells. Long-term tumour shrinkage is observable when this constraint is met; otherwise, treatment fails. Our results suggest that stem cell specificity of an oncolytic virus depends both on the average infectivity and mitotic rates of infected cells. There is a positive correlation between the average infectivity rate and stem cell specificity for nonmitotic infected cells: when average infectivity is high, an oncolytic virus with higher stem cell specificity leads to smaller tumours. In contrast, when average infectivity is low, the minimum tumour size is obtained when an oncolytic virus with higher potency targeting differentiated cells is used. For the perfect stem cell targeting regimen, we derive the condition that leads to the minimum tumour size.

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