Dataset Information

Jenner2018 - treatment of oncolytic virus

ABSTRACT: The paper describes a model of oncolytic virotherapy. Created by COPASI 4.26 (Build 213) This model is described in the article: Mathematical Modelling of the Interaction Between Cancer Cells and an Oncolytic Virus: Insights into the Effects of Treatment Protocols Adrianne L. Jenner, Chae-Ok Yun, Peter S. Kim, Adelle C. F. Coster Bull Math Biol (2018) 80:1615–1629 Abstract: Oncolyticvirotherapyisanexperimentalcancertreatmentthatusesgenet- ically engineered viruses to target and kill cancer cells. One major limitation of this treatment is that virus particles are rapidly cleared by the immune system, preventing them from arriving at the tumour site. To improve virus survival and infectivity Kim et al. (Biomaterials 32(9):2314–2326, 2011) modified virus particles with the polymer polyethylene glycol (PEG) and the monoclonal antibody herceptin. Whilst PEG mod- ification appeared to improve plasma retention and initial infectivity, it also increased the virus particle arrival time. We derive a mathematical model that describes the inter- action between tumour cells and an oncolytic virus. We tune our model to represent the experimental data by Kim et al. (2011) and obtain optimised parameters. Our model provides a platform from which predictions may be made about the response of cancer growth to other treatment protocols beyond those in the experiments. Through model simulations, we find that the treatment protocol affects the outcome dramatically. We quantify the effects of dosage strategy as a function of tumour cell replication and tumour carrying capacity on the outcome of oncolytic virotherapy as a treatment. The relative significance of the modification of the virus and the crucial role it plays in optimising treatment efficacy are explored. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

SUBMITTER: Jinghao Men

PROVIDER: BIOMD0000000789 | BioModels | 2021-03-12

REPOSITORIES: BioModels

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Publications

Mathematical Modelling of the Interaction Between Cancer Cells and an Oncolytic Virus: Insights into the Effects of Treatment Protocols.

Jenner Adrianne L AL Yun Chae-Ok CO Kim Peter S PS Coster Adelle C F ACF

Bulletin of mathematical biology 20180411 6

Oncolytic virotherapy is an experimental cancer treatment that uses genetically engineered viruses to target and kill cancer cells. One major limitation of this treatment is that virus particles are rapidly cleared by the immune system, preventing them from arriving at the tumour site. To improve virus survival and infectivity Kim et al. (Biomaterials 32(9):2314-2326, 2011) modified virus particles with the polymer polyethylene glycol (PEG) and the monoclonal antibody herceptin. Whilst PEG modif ...[more]

PMID: 29644518

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Project description:This mathematical model of the role of the innate immune responses generated by macrophages in the context of anti-tumour oncolytic viral therapies is described in the publication: Nada Almuallem, Dumitru Trucu, Raluca Eftimie. "Oncolytic viral therapies and the delicate balance between virus-macrophage-tumour interactions: A mathematical approach". Mathematical Biosciences and Engineering, 2021, 18(1): 764-799. doi: 10.3934/mbe.2021041 Comment: This model is represented by Equations 2.1a-f of the publication manuscript. Abstract: The success of oncolytic virotherapies depends on the tumour microenvironment, which contains a large number of infiltrating immune cells. In this theoretical study, we derive an ODE model to investigate the interactions between breast cancer tumour cells, an oncolytic virus (Vesicular Stomatitis Virus), and tumour-infiltrating macrophages with different phenotypes which can impact the dynamics of oncolytic viruses. The complexity of the model requires a combined analytical-numerical approach to understand the transient and asymptotic dynamics of this model. We use this model to propose new biological hypotheses regarding the impact on tumour elimination/relapse/persistence of: (i) different macrophage polarisation/re-polarisation rates; (ii) different infection rates of macrophages and tumour cells with the oncolytic virus; (iii) different viral burst sizes for macrophages and tumour cells. We show that increasing the rate at which the oncolytic virus infects the tumour cells can delay tumour relapse and even eliminate tumour. Increasing the rate at which the oncolytic virus particles infect the macrophages can trigger transitions between steady-state dynamics and oscillatory dynamics, but it does not lead to tumour elimination unless the tumour infection rate is also very large. Moreover, we confirm numerically that a large tumour-induced M1→M2 polarisation leads to fast tumour growth and fast relapse (if the tumour was reduced before by a strong anti-tumour immune and viral response). The increase in viral-induced M2→M1 re-polarisation reduces temporarily the tumour size, but does not lead to tumour elimination. Finally, we show numerically that the tumour size is more sensitive to the production of viruses by the infected macrophages.

Project description:Replicating viruses have broad applications in biomedicine, notably in cancer virotherapy and in the design of attenuated vaccines, however uncontrolled virus replication in vulnerable tissues can give pathology and often restricts the use of potent strains. Increased knowledge of tissue-selective microRNA expression now affords the possibility of engineering replicating viruses that are attenuated at the RNA level in sites of potential pathology, but retain wild type replication activity at sites not expressing the relevant microRNA. To assess the usefulness of this approach for the DNA virus, adenovirus, we have engineered a hepatocyte-safe wild type adenovirus 5 (Ad5), which normally mediates significant toxicity and is potentially lethal in mice. To do this we have included binding sites for hepatocyte-selective microRNA122a within the 3' UTR of the E1A transcription cassette. Imaging versions of these viruses, produced by fusing E1A with luciferase, showed that inclusion of microRNA122a binding sites caused up to 80 fold decreased hepatic expression of E1A following intravenous delivery to mice. Animals administered a ten-times lethal dose of wild type Ad5 (5 x 1010 viral particles/mouse) showed substantial hepatic genome replication and extensive liver pathology, while inclusion of 4 microRNA binding sites decreased replication 50-fold and virtually abrogated liver toxicity. This modified wild type virus retained full activity within cancer cells and provides a potent, liver-safe oncolytic virus. In addition to providing many potent new viruses for cancer virotherapy, microRNA-control of virus replication should provide a new strategy for designing safe attenuated vaccines applied across a broad range of viral diseases. four groups which we had were: WT: RNA extracted from livers of mice treated with wild type Ad5, 3 Replicates miR: RNA extracted from livers of mice treated with wild type Ad5 bearing mir122-binding sites in the 3'UTR of E1A (3 Replicates) Luc: RNA extracted from livers of mice treated with non-replicating Ad5 (3 Replicates) PBS: RNA extracted from livers of mice treated with PBS only (3 Replicates)

Dataset Information

Jenner2018 - treatment of oncolytic virus

Publications

Mathematical Modelling of the Interaction Between Cancer Cells and an Oncolytic Virus: Insights into the Effects of Treatment Protocols.

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