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Oncolytic Virotherapy for the Treatment of Non-Hodgkin Lymphoma

Holmes, Matthew (2018) Oncolytic Virotherapy for the Treatment of Non-Hodgkin Lymphoma. PhD thesis, University of Leeds.

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Abstract

Non-Hodgkin Lymphoma (NHL) is a diverse group of more than 80 predominantly B cell cancers of the lymphatic system. Poor survival rates in aggressive subsets, the transformation of indolent subsets into aggressive forms, and the emergence of therapy-resistance warrants research into novel therapies. Oncolytic viruses (OV) preferentially replicate in and kill malignant cells. Here we investigate the efficacy of two OV, reovirus Type 3 Dearing and Coxsackievirus Type A21 (CVA21), against NHL cell lines and primary patient samples, examine the role of the tumour microenvironment in virus susceptibility, characterise the cellular determinants of CVA21 infection of malignant cells and test the ability of both viruses to potentiate an immune response against NHL, alone or in combination with monoclonal antibodies (mAbs). CD40L on T cells can signal through CD40 on NHL B cells, resulting in pro-survival signals that induce resistance to standard chemotherapy. CD40L stimulation induced vincristine resistance in NHL cell lines but enhanced CVA21-induced cell death, implying a role for CVA21 in targeting drug-resistant NHL cells. CD40L stimulation and had no effect on reovirus-induced cell death. To investigate possible determinants of CVA21 susceptibility, the effects of the interferon (IFN) response and mTOR pathway on CVA21-induced cell death of NHL cells were investigated. Despite possessing an intact IFN response, NHL cell lines remained susceptible to CVA21 infection, suggesting that CVA21 may utilise mechanisms to subvert the antiviral IFN response. Moreover, mTOR inhibition by rapamycin reduced CVA21-induced cell death in NHL cell lines, demonstrating the importance of mTOR signalling for CVA21-induced cell death. MAbs bind to their cognate antigen and mark cells for destruction by immune cells and have shown promising results in combination with OV in a variety of malignancies. Anti-CD20 antibodies, such as rituximab, target CD20 on NHL cells and are being investigated in combination with OV for haematological malignancies, such as Chronic Lymphocytic Leukaemia (CLL). CVA21, reovirus and our candidate anti-CD20 antibody, BHH2, induced NK cell recognition of NHL cell lines as single agents. This targeting was enhanced in some cell lines when either virus was used in combination with BHH2, outlining a potential role for an OV-mAb combination for the treatment of NHL. Importantly, CD40L stimulation and the induction of a drug-resistant phenotype did not impair recognition of NHL cell lines by OV activated NK cells. The results reported here outline a promising role for CVA21, but not reovirus, as a potent lytic agent against NHL cells. This data also implicates both reovirus and CVA21 as potent immunogenic agents that can induce NK cell targeting of NHL cell lines alone and in combination with anti-CD20 mAbs.

Item Type: Thesis (PhD)
Academic Units: The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Experimental Oncology
Depositing User: Mr Matthew Holmes
Date Deposited: 27 Nov 2018 12:51
Last Modified: 27 Nov 2018 12:51
URI: http://etheses.whiterose.ac.uk/id/eprint/22218

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