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

Uusi-Kerttula, H. et al. (2018) Ad5NULL-A20: a tropism-modified, αvβ6 integrin-selective oncolytic adenovirus for epithelial ovarian cancer therapies. Clinical Cancer Research, 24(17), pp. 4215-4224. (doi: 10.1158/1078-0432.CCR-18-1089) (PMID:29798908)

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Abstract

Purpose: Virotherapies are maturing in the clinical setting. Adenoviruses (Ad) are excellent vectors for the manipulability and tolerance of transgenes. Poor tumor selectivity, off-target sequestration, and immune inactivation hamper clinical efficacy. We sought to completely redesign Ad5 into a refined, tumor-selective virotherapy targeted to αvβ6 integrin, which is expressed in a range of aggressively transformed epithelial cancers but nondetectable in healthy tissues. Experimental Design: Ad5NULL-A20 harbors mutations in each major capsid protein to preclude uptake via all native pathways. Tumor-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 preexisting anti-Ad5 immunity. In vivo biodistribution of Ad5NULL-A20 following systemic delivery in non–tumor-bearing mice was significantly reduced in all off-target organs, including a remarkable 107-fold reduced genome accumulation in the liver compared with Ad5. Tumor 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 with those treated with oncolytic Ad5. Conclusions: Oncolytic Ad5NULL-A20 virotherapies represent an excellent vector for local and systemic targeting of αvβ6-overexpressing cancers and exciting platforms for tumor-selective overexpression of therapeutic anticancer modalities, including immune checkpoint inhibitors.

Item Type:Articles
Additional Information:H. Uusi-Kerttula was supported by a Cancer Research Wales PhD studentship to A.L. Parker, J.A. Davies is supported by a Cancer Research UK Biotherapeutics Drug Discovery Project Award to A.L. Parker (project reference C52915/A23946). A.T. Baker is supported by a Tenovus Cancer Care PhD studentship to A.L. Parker (project reference PhD2015/L13). A.L. Parker is funded by Higher Education Funding Council for Wales.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bradshaw, Dr Angela
Authors: Uusi-Kerttula, H., Davies, J. A., Thompson, J., Wongthida, P., Evgin, L., Shim, K. G., Bradshaw, A., Baker, A. T., Rizkallah, P. J., Jones, R., Hanna, L., Hudson, E., Vile, R., Chester, J. D., and Parker, A. L.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Clinical Cancer Research
Publisher:American Association for Cancer Research
ISSN:1078-0432
ISSN (Online):1557-3265
Published Online:24 May 2018
Copyright Holders:Copyright © 2018 American Association for Cancer Research
First Published:First published in Clinical Cancer Research 24(17): 4215-4224
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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