Cargando…

Modelling the spatial dynamics of oncolytic virotherapy in the presence of virus-resistant tumour cells

Oncolytic virotherapy is a promising form of cancer treatment that uses native or genetically engineered viruses to target, infect and kill cancer cells. Unfortunately, this form of therapy is not effective in a substantial proportion of cancer patients, partly due to the occurrence of infection-res...

Descripción completa

Detalles Bibliográficos
Autores principales: Bhatt, Darshak Kartikey, Janzen, Thijs, Daemen, Toos, Weissing, Franz J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9767357/
https://www.ncbi.nlm.nih.gov/pubmed/36473017
http://dx.doi.org/10.1371/journal.pcbi.1010076
_version_ 1784853949170319360
author Bhatt, Darshak Kartikey
Janzen, Thijs
Daemen, Toos
Weissing, Franz J.
author_facet Bhatt, Darshak Kartikey
Janzen, Thijs
Daemen, Toos
Weissing, Franz J.
author_sort Bhatt, Darshak Kartikey
collection PubMed
description Oncolytic virotherapy is a promising form of cancer treatment that uses native or genetically engineered viruses to target, infect and kill cancer cells. Unfortunately, this form of therapy is not effective in a substantial proportion of cancer patients, partly due to the occurrence of infection-resistant tumour cells. To shed new light on the mechanisms underlying therapeutic failure and to discover strategies that improve therapeutic efficacy we designed a cell-based model of viral infection. The model allows us to investigate the dynamics of infection-sensitive and infection-resistant cells in tumour tissue in presence of the virus. To reflect the importance of the spatial configuration of the tumour on the efficacy of virotherapy, we compare three variants of the model: two 2D models of a monolayer of tumour cells and a 3D model. In all model variants, we systematically investigate how the therapeutic outcome is affected by the properties of the virus (e.g. the rate of viral spread), the tumour (e.g. production rate of resistant cells, cost of resistance), the healthy stromal cells (e.g. degree of resistance to the virus) and the timing of treatment. We find that various therapeutic outcomes are possible when resistant cancer cells arise at low frequency in the tumour. These outcomes depend in an intricate but predictable way on the death rate of infected cells, where faster death leads to rapid virus clearance and cancer persistence. Our simulations reveal three different causes of therapy failure: rapid clearance of the virus, rapid selection of resistant cancer cells, and a low rate of viral spread due to the presence of infection-resistant healthy cells. Our models suggest that improved therapeutic efficacy can be achieved by sensitizing healthy stromal cells to infection, although this remedy has to be weighed against the toxicity induced in the healthy tissue.
format Online
Article
Text
id pubmed-9767357
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-97673572022-12-21 Modelling the spatial dynamics of oncolytic virotherapy in the presence of virus-resistant tumour cells Bhatt, Darshak Kartikey Janzen, Thijs Daemen, Toos Weissing, Franz J. PLoS Comput Biol Research Article Oncolytic virotherapy is a promising form of cancer treatment that uses native or genetically engineered viruses to target, infect and kill cancer cells. Unfortunately, this form of therapy is not effective in a substantial proportion of cancer patients, partly due to the occurrence of infection-resistant tumour cells. To shed new light on the mechanisms underlying therapeutic failure and to discover strategies that improve therapeutic efficacy we designed a cell-based model of viral infection. The model allows us to investigate the dynamics of infection-sensitive and infection-resistant cells in tumour tissue in presence of the virus. To reflect the importance of the spatial configuration of the tumour on the efficacy of virotherapy, we compare three variants of the model: two 2D models of a monolayer of tumour cells and a 3D model. In all model variants, we systematically investigate how the therapeutic outcome is affected by the properties of the virus (e.g. the rate of viral spread), the tumour (e.g. production rate of resistant cells, cost of resistance), the healthy stromal cells (e.g. degree of resistance to the virus) and the timing of treatment. We find that various therapeutic outcomes are possible when resistant cancer cells arise at low frequency in the tumour. These outcomes depend in an intricate but predictable way on the death rate of infected cells, where faster death leads to rapid virus clearance and cancer persistence. Our simulations reveal three different causes of therapy failure: rapid clearance of the virus, rapid selection of resistant cancer cells, and a low rate of viral spread due to the presence of infection-resistant healthy cells. Our models suggest that improved therapeutic efficacy can be achieved by sensitizing healthy stromal cells to infection, although this remedy has to be weighed against the toxicity induced in the healthy tissue. Public Library of Science 2022-12-06 /pmc/articles/PMC9767357/ /pubmed/36473017 http://dx.doi.org/10.1371/journal.pcbi.1010076 Text en © 2022 Bhatt et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Bhatt, Darshak Kartikey
Janzen, Thijs
Daemen, Toos
Weissing, Franz J.
Modelling the spatial dynamics of oncolytic virotherapy in the presence of virus-resistant tumour cells
title Modelling the spatial dynamics of oncolytic virotherapy in the presence of virus-resistant tumour cells
title_full Modelling the spatial dynamics of oncolytic virotherapy in the presence of virus-resistant tumour cells
title_fullStr Modelling the spatial dynamics of oncolytic virotherapy in the presence of virus-resistant tumour cells
title_full_unstemmed Modelling the spatial dynamics of oncolytic virotherapy in the presence of virus-resistant tumour cells
title_short Modelling the spatial dynamics of oncolytic virotherapy in the presence of virus-resistant tumour cells
title_sort modelling the spatial dynamics of oncolytic virotherapy in the presence of virus-resistant tumour cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9767357/
https://www.ncbi.nlm.nih.gov/pubmed/36473017
http://dx.doi.org/10.1371/journal.pcbi.1010076
work_keys_str_mv AT bhattdarshakkartikey modellingthespatialdynamicsofoncolyticvirotherapyinthepresenceofvirusresistanttumourcells
AT janzenthijs modellingthespatialdynamicsofoncolyticvirotherapyinthepresenceofvirusresistanttumourcells
AT daementoos modellingthespatialdynamicsofoncolyticvirotherapyinthepresenceofvirusresistanttumourcells
AT weissingfranzj modellingthespatialdynamicsofoncolyticvirotherapyinthepresenceofvirusresistanttumourcells