Immunotherapy for the treatment of poor prognosis cancers

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dc.check.date10000-01-01
dc.check.embargoformatNot applicableen
dc.check.infoNo embargo requireden
dc.check.opt-outYesen
dc.check.reasonNo embargo requireden
dc.check.typeThe full text of this thesis is unavailable due to a restriction requested by the author.
dc.contributor.advisorSoden, Declanen
dc.contributor.advisorForde, Patricken
dc.contributor.authorO'Brien, Morgan Anthony
dc.contributor.funderBreakthrough Cancer Research, Irelanden
dc.date.accessioned2016-05-09T15:21:30Z
dc.date.available2016-05-09T15:21:30Z
dc.date.issued2016
dc.date.submitted2016
dc.description.abstractCancer 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.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationO'Brien, M. A. 2016. Immunotherapy for the treatment of poor prognosis cancers. PhD Thesis, University College Cork.en
dc.identifier.urihttps://hdl.handle.net/10468/2527
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2016, Morgan A. O'Brien.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectImmunotherapyen
dc.subjectCTLA-4en
dc.subjectPD-1en
dc.subjectiCOSen
dc.subjectImmunoeditingen
dc.subjectBiochemistryen
dc.subjectMetastasisen
dc.subjectCytotoxic T cellsen
dc.subjectB cellsen
dc.subjectAntigen-specific antibodiesen
dc.subjectCytokinesen
dc.subjectIntracellular signallingen
dc.subjectImmune checkpoint blockadeen
dc.subjectMonoclonal antibodiesen
dc.subjectCancer immunologyen
dc.subjectInflammatory profileen
dc.subjectTumour biologyen
dc.subjectMolecular biologyen
dc.subjectAbscopal effecten
dc.subjectImmunogenic cell deathen
dc.subjectDamage associated molecular proteinsen
dc.subjectTumour associated antigensen
dc.subjectTumour specific immunityen
dc.thesis.opt-outtrue
dc.titleImmunotherapy for the treatment of poor prognosis cancersen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Medicine and Health)en
ucc.workflow.supervisord.soden@ucc.ie
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