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Breast Cancer Immunotherapy Using Magnetised Oncolytic Virus

Al-Janabi, Haider (2019) Breast Cancer Immunotherapy Using Magnetised Oncolytic Virus. PhD thesis, University of Sheffield.

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Abstract

Abstract Background: Oncolytic viruses (OV) are encouraging new immunotherapies for cancer. OVs, replicate in cancer cells inducing immunogenic cell death (ICD) and activating antitumour immunity. To date, clinical use has focused on intratumoural delivery due to concerns over inadequate tumour targeting following systemic administration. We hypothesise that magnetising OVs and magnetic guidance strategies will improve their systemic delivery by protecting the viruses from inactivating immune mechanisms but at the same time promote anti-tumour immunity. Methods: To investigate this, we synthesised and characterised complexes of magnetised oncolytic herpes simplex virus (HSV1716) co-assembled with biocompatible magnetic nanoparticles (MAG) derived from magnetotactic bacteria (AMB-1) to give MAG-OV complexes. Characterization of the physical, chemical and oncolytic potential of MAG-OV was performed. The safety and efficacy of this nanomedicine in combination with magnetic guidance strategies was assessed in vivo. Results: Stable MAG-OV complexes of ~160nm diameter successfully infected human and murine breast cancer cells in a dose-dependent manner, and induced tumour oncolysis. Following MAG-OV infection a significant increase in viral replication (ICP0, gB, ICP8), ICD (HMGB1, CALR, ATP) and apoptotic (CASP 3, CASP8, FASL) signals were detected. Intravenous delivery of MAG-OV resulted in reduced tumour burden in the presence of magnetic guidance (MAG-OV 448.3mm³ vs. HSV1716 670.6mm³; p ≤ 0.05, n=6-9 mice/group) and an increase in tumour-infiltrating T-cells, NK cells and neutrophils. Furthermore, MAG-OV were protective in the presence of neutralising Abs both in vitro and in vivo. Conclusion: This study indicates that MAG are more small and uniform in size and form complexes with OV in such a way that the virus does not change its properties. MAG-OV is able to enter and replicate inside breast cancer cells, at the same time inducing tumour cell death as good as OV alone but with the addition of protecting the virus from neutralising Ab and in combination with magnetic guidance reduces tumour burden and induces anti-tumour immunity.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Depositing User: MR Haider Al-Janabi
Date Deposited: 19 Aug 2019 08:00
Last Modified: 19 Aug 2019 08:00
URI: http://etheses.whiterose.ac.uk/id/eprint/24669

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