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Title: The role of oncolytic virus-induced anti-tumour immunity in haematological malignancies
Author: Müller, Louise Marie Erika
ISNI:       0000 0004 7960 2935
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2018
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Haematological malignancies (HM) are a diverse group of relatively rare, but often life-threatening cancers. Over 900 000 people worldwide are expected to receive a HM diagnosis in 2018. Most types of HM have an increasing incidence with age, which is often associated with poor survival due to the inadequate treatment options available. Two types of HM with a particularly poor outlook are acute myeloid leukaemia (AML), which is an acute cancer of immature myeloid blood cells, and multiple myeloma (MM) which is an incurable malignancy with primary focus in the bone marrow (BM). Oncolytic viruses (OV) preferentially infect and kill malignantly transformed cells. OV therapy (OVT) is a promising treatment strategy which has recently been approved for clinical use in the treatment of melanoma. In addition to direct lytic killing, the induction of an anti-tumour immune response is thought to be essential for efficient OVT with establishment of long-term protection against tumour recurrence. While research efforts into OVT for solid malignancies have seen a surge in recent years, HM remains under-investigated in this context, in particular with regards to the anti-tumour immune response. Thus, the overall aim of this study was to examine the role of OV-induced anti-tumour immunity in HM. Two OV were evaluated in the context of MM; both reovirus and coxsackievirus A21 (CVA21) were found to induce anti-tumour immune responses in vitro comprising cytokine-mediated killing, natural killer cellmediated cytotoxicity, and the generation of tumour-specific cytotoxic T cells. Moreover, reovirus treatment showed efficacy in an immunocompetent in vivo model, along with evidence of the onset of an immune response primarily in the spleen. Pivotally, this study is the first to evaluate CVA21 as a treatment for AML. CVA21 was able to induce anti-tumour immunity in AML in vitro using both AML cell lines and a cohort of primary AML samples, despite resistance to lytic killing. Furthermore, examination of peripheral blood samples from patients with solid malignancies following intravenous administration of CVA21 provided "proof of principle" evidence that CVA21 was able to activate immune cells in the peripheral circulation in a state of malignancy, which is crucial for the future development of CVA21 OVT. The obtained results also established the cellular mechanisms responsible for CVA21-induced anti-tumour immunity. Plasmacytoid dendritic cells were identified as the main detectors of CVA21 infection and were responsible for orchestrating both innate and adaptive anti-tumour immune responses. These findings provide novel insights into the immunobiology of CVA21 with importance for the continued clinical development of this OV. In conclusion, this study has demonstrated that OVT, as a well-tolerated, specific, and long-lasting therapy, has the potential to improve the treatment of both MM and AML through the induction of a multi-component anti-tumour immune response.
Supervisor: Errington-Mais, Fiona ; Cook, Gordon ; Scott, Gina Sponsor: Leeds Institute of Cancer & Pathology
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available