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Development of ovarian cancer-targeted adenoviral vectors

Uusi-Kerttula, Hanni 2017. Development of ovarian cancer-targeted adenoviral vectors. PhD Thesis, Cardiff University.
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Abstract

Ovarian cancer is the deadliest gynaecological cancer, with less than half of patients surviving five years from diagnosis. The asymptomatic nature of the early disease commonly results in diagnosis at an advanced stage where peritoneal metastases are prevalent, and the disease rapidly develops resistance to platinum-based agents. Innovative treatments are needed to combat this untreatable disease that has a poor prognosis. Adenoviruses (Ad) are versatile gene therapy vehicles that have been studied for six decades. Their wider clinical use has been limited by poor tumour-specificity, pre-existing immunity, and toxicity-inducing off-target delivery. We have generated an Ad5.3D.A20 vector that is re-targeted to an epithelial cancer-specific marker, αvβ6 integrin, and fully de-targeted from native interactions ‒ αvβ3/5 integrins, coxsackie and adenovirus receptor (CAR), and human coagulation factor 10 (FX). Ad5.3D.A20 selectively transduced αvβ6+ epithelial ovarian cancer (EOC) cells in vitro and clinical ovarian ascites-derived EOC cells ex vivo, including in the presence of neutralising anti-Ad antibodies. In vivo, Ad5.3D.A20 exhibited significantly reduced off-target accumulation and transduction of the liver, spleen and lungs, relative to Ad5. Efficacy studies are underway to investigate its oncolytic potential. Furthermore, we explored the potential use of alternative serotypes from the rare seroprevalence subgroup D. A novel Ad10 vector showed improved resistance from neutralisation and lack of FX binding. Chimaeric Ad5 vectors pseudotyped with Ad10, -15, -24, -29, -48 or -53 fiber had reduced interactions with CAR, but no binding to CD46. Our strategy for translation initially is via intraperitoneal delivery of oncolytic vectors, bypassingmany of the barriers presented by systemic delivery, but enabling transduction of disseminated metastases. These exquisitely tumour-targeted vectors may be further modulated to carry therapeutic moieties to complement their direct cell-killing activity via the stimulation of anti-cancer immunity. The generated tropism-modified vectors have significant therapeutic potential for a wide range of immuno-oncolytic applications.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Date of First Compliant Deposit: 2 May 2017
Last Modified: 12 Jun 2019 02:59
URI: http://orca-mwe.cf.ac.uk/id/eprint/100129

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