Dey, A; (2016) Enhancing the neutrophil-mediated anti-cancer response after oncolytic measles virus therapy in B cell malignancy: dissecting out the mechanism. Doctoral thesis , UCL (University College London).

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Abstract

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.

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