Castleton, AZ; (2014) Oncolytic measles virus and mesenchymal stromal cells: A therapeutic model and a dissection of mechanisms of action. Doctoral thesis , UCL (University College London).

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Abstract

Live, attenuated measles virus (MV) has demonstrated tumour-specific replication and anti-tumour activity in murine models of hematological and non-hematological malignancy, leading to a number of published or on-going clinical trials. However, the potentially overriding issue of how to achieve successful administration of oncolytic measles virotherapy in patients with intact humoral immunity remains. I have examined mechanisms for optimizing delivery of oncolytic MV to acute lymphoblastic leukaemia (ALL) – a disseminated haematological malignancy. Anti MV antibody titres in adult patients with ALL were evaluated before and after leukaemia treatment regimens including high dose corticosteroids, cyclophosphamide and anti-B cell monoclonal antibodies. Antibody titres were unaffected by induction and intensification treatment protocols, suggesting the need for consideration of optimal virotherapy delivery strategies to achieve therapeutic success. Here, I demonstrate that human bone marrow-derived mesenchymal stromal cells (BM-MSCs) can be used effectively as virus delivery vehicles, permitting ex-vivo cellular virus loading and intracellular virus amplification, delivery of virus to distant sites of disease following systemic infusion, and virus hand-off to precursor B lineage ALL cell targets in the presence of pre-existing anti-MV antibodies. In vivo modelling using SCID mice bearing disseminated pre-B ALL xenografts demonstrated enhanced survival of passively immunized animals following IV treatment with BM-MSC-delivered MV versus naked MV or BM-MSCs alone. In order for vaccine MV to be safely and rationally utilized as a novel therapeutic for ALL, a detailed mechanistic understanding of how the virus exerts its oncolytic effect is paramount. In this thesis, I have utilized a previously characterized model of cellular transformation generated using human BM-MSCs to characterize the phenomenon of relative tumour cell specificity by oncolytic MV, in terms of infectivity, productivity and cell killing. Furthermore, this thesis begins to explore some of the potential mechanisms that confer vaccine MV its tumour-tropic and anti-cancer properties.

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