Immunotherapy for the treatment of poor prognosis cancers

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dc.contributor.advisor Soden, Declan en
dc.contributor.advisor Forde, Patrick en O'Brien, Morgan Anthony 2016-05-09T15:21:30Z 2016-05-09T15:21:30Z 2016 2016
dc.identifier.citation O'Brien, M. A. 2016. Immunotherapy for the treatment of poor prognosis cancers. PhD Thesis, University College Cork. en
dc.description.abstract Cancer is amongst the leading causes of death worldwide and the number one cause in the developed world. Every year there are close to 10 million cancer related deaths and this corresponds to hundreds of millions of euro in health care costs and lost productivity, placing a substantial drain on the economy. The efficacy of traditional treatment modalities for cancer therapy, such as surgery, radiotherapy and chemotherapy has plateaued, and while they are undoubtedly effective at prolonging patient lifespan, there is a high rate of adverse side effects and fatal reoccurrence. Currently, there is a huge amount of interest in the areas of cancer immunosurveillance and cancer immuno-editing, which explain some of the complex interactions between the host immune system and cancer. If left unchecked, cancerous malignancies have the ability to generate an immunosuppressive microenvironment, effectively shielding themselves from elimination and promoting tumour growth and progression. To overcome this, the potential of the immune system must be harnessed and the work undertaken in this thesis sought to contribute to this goal. Focus was placed on using novel therapies, combining tumour ablation with immune-modulating antibodies to maximise tumour elimination in an immune dependent manner, to overcome immunosuppression and promote immune activation. Chapter 2 focuses on the use of ECT as a method of tumour ablation and its effects on the immune system. ECT proved to be effective at inhibiting the tumour growth both in vitro and in vivo, and conferred significant survival advantages in both small and large animal models. More importantly, ECT proved to cause tumour death in an immune dependent manner, displaying the hallmarks of Immunogenic Cell Death, increases in immune cell infiltration and generating tumour-specific immune responses. Chapter 3 focuses on combining ECT with immune checkpoint blockade inhibitors; anti- CTLA-4 and anti-PD-1. Both combinations proved to be effective at inhibiting both primary and distal tumour growth, indicating the generation of tumour specific immune responses and prolonged animal survival. In addition, the treatments caused increases in the levels of certain intra-tumoural immune cell subsets and modulated the cytokine profile of treated animals in a way that was favourable overall. Chapter 4 focuses on the combining ECT with an anti-iCOS agonist antibody, capable of causing immune co-stimulation. This novel combinational therapy proved to be the most effective by far, with a high cure rate achieved across a number of different in vivo tumour models. Total regression was seen in both primary and distal tumours, as well as spontaneous metastases, with the tumour specific immune response generated conferring total protection to animals on tumour rechallenge. Overall the data presented here adds further insight into the area of cancer immunotherapy with some of the novel combinational therapies demonstrating substantial clinic potential. en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2016, Morgan A. O'Brien. en
dc.rights.uri en
dc.subject Immunotherapy en
dc.subject CTLA-4 en
dc.subject PD-1 en
dc.subject iCOS en
dc.subject Immunoediting en
dc.subject Biochemistry en
dc.subject Metastasis en
dc.subject Cytotoxic T cells en
dc.subject B cells en
dc.subject Antigen-specific antibodies en
dc.subject Cytokines en
dc.subject Intracellular signalling en
dc.subject Immune checkpoint blockade en
dc.subject Monoclonal antibodies en
dc.subject Cancer immunology en
dc.subject Inflammatory profile en
dc.subject Tumour biology en
dc.subject Molecular biology en
dc.subject Abscopal effect en
dc.subject Immunogenic cell death en
dc.subject Damage associated molecular proteins en
dc.subject Tumour associated antigens en
dc.subject Tumour specific immunity en
dc.title Immunotherapy for the treatment of poor prognosis cancers en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Medicine and Health) en
dc.internal.availability Full text not available en No embargo required en 10000-01-01
dc.description.version Accepted Version
dc.contributor.funder Breakthrough Cancer Research, Ireland en
dc.description.status Not peer reviewed en Medicine en
dc.check.type The full text of this thesis is unavailable due to a restriction requested by the author.
dc.check.reason No embargo required en
dc.check.opt-out Yes en
dc.thesis.opt-out true
dc.check.embargoformat Not applicable en
dc.internal.conferring Summer 2016 en

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© 2016, Morgan A. O'Brien. Except where otherwise noted, this item's license is described as © 2016, Morgan A. O'Brien.
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