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Ad5NULL-A20 - a tropism-modified, αvβ6 integrin-selective oncolytic adenovirus for epithelial ovarian cancer therapies

Uusi-Kerttula, Hanni, Davies, James A, Thompson, Jill, Wongthida, Phonphimon, Evgin, Laura, Shim, Kevin G., Bradshaw, Angela, Baker, Alexander T, Rizkallah, Pierre J, Jones, Rachel, Hanna, Louise, Hudson, Emma, Vile, Richard, Chester, John D and Parker, Alan L 2018. Ad5NULL-A20 - a tropism-modified, αvβ6 integrin-selective oncolytic adenovirus for epithelial ovarian cancer therapies. Clinical Cancer Research 24 (17) , pp. 4215-4224. 10.1158/1078-0432.CCR-18-1089

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Abstract

Purpose: Virotherapies are maturing in the clinical setting. Adenoviruses (Ad) are excellent vectors for manipulability and tolerance of transgenes. Poor tumour-selectivity, off-target sequestration and immune inactivation hamper clinical efficacy. We sought to completely redesign Ad5 into a refined, tumour selective virotherapy targeted to αvβ6 integrin, which is expressed in a range of aggressively transformed epithelial cancers but non-detectable in healthy tissues. Experimental Design: Ad5NULL-A20 harbours mutations in each major capsid protein to preclude uptake via all native pathways. Tumour-tropism via αvβ6-targeting was achieved by genetic insertion of A20 peptide (NAVPNLRGDLQVLAQKVART) within the fiber knob protein. The vector's selectivity in vitro and in vivo was assessed. Results: The tropism-ablating triple mutation completely blocked all native cell entry pathways of Ad5NULL-A20 via coxsackie and adenovirus receptor (CAR), αvβ3/5 integrins and coagulation factor 10 (FX). Ad5NULL-A20 efficiently and selectively transduced αvβ6+ cell lines and primary clinical ascites-derived EOC ex vivo, including in the presence of pre-existing anti-Ad5 immunity. In vivo biodistribution of Ad5NULL-A20 following systemic delivery in non-tumour-bearing mice was significantly reduced in all off-target organs, including a remarkable 107-fold reduced genome accumulation in the liver compared to Ad5. Tumour uptake, transgene expression and efficacy were confirmed in a peritoneal SKOV3 xenograft model of human EOC, where oncolytic Ad5NULL-A20-treated animals demonstrated significantly improved survival compared to those treated with oncolytic Ad5. Conclusions: Oncolytic Ad5NULL-A20 virotherapies represent an excellent vector for local and systemic targeting of αvβ6-over-expressing cancers, and exciting platforms for tumour selective over-expression of therapeutic anti-cancer modalities, including immune checkpoint inhibitors.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Association for Cancer Research
ISSN: 1078-0432
Date of First Compliant Deposit: 13 June 2018
Date of Acceptance: 30 May 2018
Last Modified: 29 Aug 2019 21:14
URI: http://orca.cf.ac.uk/id/eprint/112235

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