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Title: Enhancing the neutrophil-mediated anti-cancer response after oncolytic measles virus therapy in B cell malignancy : dissecting out the mechanism
Author: Dey, A.
ISNI:       0000 0004 7230 8936
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Oncolytic measles virus (MV) is being tested in several ongoing clinical trials with encouraging results. There is a demonstrable need to explore the role of the immune system in addition to the direct oncolytic effect of MV. My laboratory has previously shown that neutrophils are involved in MV-mediated tumour regressions, becoming activated, upon MV infection. This thesis further explores the role of neutrophils, one of the key players of the innate immune system in MV oncolysis. First, I showed that acute lymphoblastic leukaemia (ALL) shows marked sensitivity to MV oncolysis (Patel, Dey et al., 2011). I attempted to enhance neutrophil function at tumour sites by generating a novel strain of MV expressing the human granulocyte colony-stimulating factor (GCSF), a known neutrophil survival factor and enhancer of antibody dependent cellular cytotoxicity (ADCC). Evaluating the effects in two different models of B-cell malignancy, I showed that neutrophil depletion abrogated the MV therapeutic effect in an in-vivo Raji - but not Nalm-6 - tumour model. MVhGCSF enhanced the oncolytic capacity of MV in the Raji model in-vivo, whereas in the Nalm-6 model, the opposite was unexpectedly the case. MVhGCSF replicated within an MV-infectable CD46 transgenic mouse model with detectable serum levels of hGCSF but no toxicity. My data suggest that a "one-size-fits-all" model of immune response to viral oncolysis is not appropriate, and each tumour target will need full characterisation for the potential of MV to generate benefit (Dey et al., 2016). 5 Next, I showed that ADCC was NOT a mechanism by which neutrophils kill MV-infected cells. Finally, I showed that MV infection of target cells can stimulate neutrophils to develop a cytotoxic effector phenotype, all aspects of which are blocked by fusion inhibition. Hence, I suggest a new mechanism for MV-mediated oncolysis; fusion between infected target cells and neutrophils.
Supervisor: Fielding, A. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available