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 |
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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 > School of Cardiovascular & Metabolic Health 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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