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Title: Immune cell carriers and humoral immunity in oncolytic virotherapy
Author: Berkeley, Robert Anthony
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2018
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Oncolytic viruses (OV) represent an emerging modality in cancer therapy. Antiviral immunity is currently viewed as a barrier to systemic OV efficacy. Approaches have been taken to promote OV activity by attenuating virus-neutralising antibodies (NAb). However, the presence of NAb does not prevent intravenously administered OV, such as reovirus, reaching tumours in patients. Recent evidence suggests that NAb may in fact support virotherapy in mice by facilitating reovirus carriage upon circulating immune cells, principally monocytes. In this thesis, the applicability of these observations to the human setting is examined, modelling the loading of monocytes with reovirus in virus-immune patients. A novel in vitro cell carriage assay was employed, involving clinical trial patient-derived sera, isolated primary human monocytes, and human tumour cell lines. It was discovered that monocytes treated with fully neutralised reovirus reliably delivered the virus to kill melanoma targets. This was transferable across target cell histologies, and applicable to another OV, CVA21. Neutralised reovirus successfully accessed syngeneic melanoma flank tumours in mice. Prior murine studies suggested a role for surface Fc receptors in facilitating the antibody-dependent enhancement (ADE) of monocyte infection. A major role for Fc receptors in antibody-mediated entry of neutralised reovirus to human monocytes was confirmed. Yet no overall enhancement of virus loading or hand-off was conferred by the presence of NAb, in contrast to existing observations from mouse monocytes. Transcriptomic and secretory profiling identified discrete variations in the effects of free and neutralised reovirus upon monocyte phenotype. NAb significantly attenuated the monocyte IFN response to reovirus in vitro. However, in the presence of monocytes, reo-NAb successfully induced NK cell degranulation and killing of melanoma targets. Therefore this study identifies a mechanism by which, following neutralisation, reovirus may rely on circulating monocytes to gain tumour access, and to initiate oncolytic and/or immune-mediated tumour cell death.
Supervisor: Ilett, Liz ; Errington-Mais, Fiona ; Melcher, Alan Sponsor: University of Leeds
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available