Expanding the use of electroporation from cutaneous to intraluminal and systemic applications
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Date
2015
Authors
Sadadcharam, Mira
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Publisher
University College Cork
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Abstract
Cancer is a global phenomenon transcending the boundaries of age, race, geography and socioeconomic background. As our understanding of cancer cell biology has improved, we have developed a growing appreciation of cancer as a systemic disease. However, our improved understanding has been matched by cancer cell evolution and it is becoming increasingly clear that the future of anti-cancer therapies lies in a multi-modal approach. In this thesis, we adopted a “three-legged stool” approach to anti-cancer therapy. The first leg encompasses primary tumour ablation. We developed the EndoVe device, enabling endoscopic electroporation of gastrointestinal tissues and tumours. We conducted a pre-clinical evaluation of the EndoVe prior to a phase I/II clinical study and validated the efficacy of the system in the treatment of cutaneous murine gastrointestinal tumours. In addition, we established the safety and utility of endoscopically-delivered electroporation through evaluation in a porcine model and by treating canine colorectal tumours. The second leg of our stool involved immunotherapy. We opted for a combination regime of Treg depletion and immunotherapy with the cytokine, pGMCSF-B7.1. While we observed a modest but significant improvement of primary tumour burden, the combination regime had the remarkable effect of eradicating pre-existing, established lung metastases when compared to the use of either treatment alone. The potential clinical implications of this should not be understated as nine out of ten cancer deaths are directly attributable to metastatic disease burden. The third and final leg of our anti-cancer strategy involved the development of a DNA-based enhanced expression vector (pEEV), with improved expression capabilities across a range of tissue histologies over standard non-viral DNA vectors. Following on from this observation, we then utilised this pEEV vector system in combination with the immune cytokine GMCSF-B7.1 leading to robust recruitment of immune effector cells with consequent potent, durable and transferable tumour antigen-specific responses.
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Keywords
Electroporation , Electrochemotherapy , EndoVe , Cancer immunogene therapy , Immune therapy , Gene therapy
Citation
Sadadcharam, M. 2015. Expanding the use of electroporation from cutaneous to intraluminal and systemic applications. PhD Thesis, University College Cork.