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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 M., 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: 15 May 2018
Last Modified: 27 Jul 2020 14:13
URI: http://orca-mwe.cf.ac.uk/id/eprint/112235

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