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Title: Immune cells as carriers of oncolytic viruses for tumor cell killing
Author: Jennings, Victoria Ann
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2012
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Ovarian cancer is the fourth most common cause of cancer death in women, with a five year survival rate of 41 %. Therefore novel therapies which supplement and enhance the efficacy of current treatment regimens are required. Oncolytic viruses (OV) are novel anti-cancer agents that replicate preferentially in tumour cells causing cell death. Reovirus is one such OV, which is currently in phase I-Ill clinical trials, demonstrating promising results. Here we investigate the use of reovirus for the treatment of ovarian cancer. Ovarian cancer is often associated with an accumulation of ascitic fluid, which can interfere with oncolytic viral therapy. Therefore the effect of ascites on reovirus cytotoxicity against ovarian cancer cell lines and primary ascites-derived tumour cells was investigated. In the absence of ascites, reovirus was cytotoxic against ovarian cancer cells; however cytotoxjcity was abrogated if ascites was present. These studies identified that neutralising antibodies (NAb) were the cause of this inhibition. Cell carriers have been used previously to protect OV from antibody neutralisation. This study investigated using immature dendritic cells (iDC), Iymphokine-activated killer (LAK) cells or LAKDC co-cultures as cell carriers to protect reovirus from neutralisation. Furthermore the ability of the cell carriers to provide additional anti-tumour responses via enhanced cytotoxicity and anti-tumour immune priming were examined. The results discussed here show that LAK cells and LAKDC were directly cytotoxic against ovarian cancer cell lines. Importantly, LAK cells could be generated from ovarian cancer patients to recognise and kill autologous tumour cells, even in the presence of high concentrations of ascites. Moreover, reovirus-loaded LAKDC or iDC were able to hand-off reovirus for tumour cell killing and generate a specific anti-tumour immune response in the presence of ascites, while neat reovirus and reovirus-loaded LAK cells were ineffective. In vivo studies to confirm the efficacy of LAKDC/reovirus therapy for ovarian cancer are discussed, however further optimisation of these models are required. These studies demonstrate the potential of reovirus-loaded LAKDC combination therapy for the treatment of ovarian cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available