Optimising Oncolytic Virotherapy and Immunotherapy for the treatment of Disseminated Colorectal Cancer

摘要: Colorectal cancer (CRC) is one of the most prevalent malignancies in Western world with a 5 year survival rate patients metastatic disease less than 10%. As such, there remains pressing need for novel treatment strategies and modalities. Established treatments including anti-EGFR antibodies, example cetuximab, have improved although disappointingly only 10-20% obtain an objective clinical response. Advancing modalities include oncolytic viruses (Reovirus, Vaccinia Virus (JX-594)), which preferentially replicate cells causing cell death stimulate anti-tumour immunity, BH3-mimetic inhibitors (ABT- 263), antagonise BCL-2 family pro-survival proteins, may enhance CRC patient survival. Harnessing potential immune anti- effects these modalities, alone combination, at primary tumour sites micrometastatic (for lymph nodes) could form basis successful adjuvant strategies. This MD thesis aims to investigate efficacy two OV, Reovirus JX- 594 vaccinia virus against CRC. In particular, work outlined this has examined whether i) directly kills lines differential mutational status, or combination BH3-mimetics ii) can activate effector killing EGFR targeted order optimise use therapy; iii) delineate mechanism induced by JX-594 treated cells, iv) test ability induce innate response blood nodes. Studies investigating ABT-263 Cetuximab were performed. demonstrated that strategy did not yield enhanced over either agent alone, additive observed single line, SW620. However, initial studies combining OV reveal increase EGFR-mediated ADCC KRAS mutant SW480, demonstrating importance activation therapeutic approaches. To date, reovirus well recognised however, known about JX-594, currently testing Leeds Teaching Hospitals NHS Trust. JX594 populations, healthy donor blood, along nodes from patients, collected JX-594. NK CD69 activation, degranulation increased cytotoxicity line targets. was dependent on IFN production presence CD14+ve monocytes however node mononuclear independent be elucidated. Importantly, reside LN encouraging targeting distant disease. OV hold promise as modality. Direct tumour-specific lysis, transgene expression induction specific immunity isolation, adjunct antitumour means they provide two-pronged attack different sites.