Ad5NULL-A20: A tropism-modified, avb6 integrin-selective oncolytic adenovirus for epithelial ovarian cancer therapies

Hanni Uusi-Kerttula, James A. Davies, Jill M. Thompson, Phonphimon Wongthida, Laura Evgin, Kevin G. Shim, Angela Bradshaw, Alexander T. Baker, Pierre J. Rizkallah, Rachel Jones, Louise Hanna, Emma Hudson, Richard Geoffrey Vile, John D. Chester, Alan L. Parker

Research output: Contribution to journalArticle

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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 avb6 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 avb6 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), avb3/5 integrins, and coagulation factor 10 (FX). Ad5NULL-A20 efficiently and selectively transduced avb6þ 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 avb6-overexpressing cancers and exciting platforms for tumor-selective overexpression of therapeutic anticancer modalities, including immune checkpoint inhibitors.

Original languageEnglish (US)
Pages (from-to)4215-4224
Number of pages10
JournalClinical Cancer Research
Volume24
Issue number17
DOIs
StatePublished - Sep 1 2018

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Tropism
Adenoviridae
Integrins
Neoplasms
Transgenes
Therapeutics
Coxsackie and Adenovirus Receptor-Like Membrane Protein
Mutation
Blood Coagulation Factors
Capsid Proteins
Ovarian epithelial cancer
Ascites
Heterografts
Immunity
Research Design
Genome
Cell Line
Peptides
Survival
Liver

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Uusi-Kerttula, H., Davies, J. A., Thompson, J. M., Wongthida, P., Evgin, L., Shim, K. G., ... Parker, A. L. (2018). Ad5NULL-A20: A tropism-modified, avb6 integrin-selective oncolytic adenovirus for epithelial ovarian cancer therapies. Clinical Cancer Research, 24(17), 4215-4224. https://doi.org/10.1158/1078-0432.CCR-18-1089

Ad5NULL-A20 : A tropism-modified, avb6 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 Geoffrey; Chester, John D.; Parker, Alan L.

In: Clinical Cancer Research, Vol. 24, No. 17, 01.09.2018, p. 4215-4224.

Research output: Contribution to journalArticle

Uusi-Kerttula, H, Davies, JA, Thompson, JM, Wongthida, P, Evgin, L, Shim, KG, Bradshaw, A, Baker, AT, Rizkallah, PJ, Jones, R, Hanna, L, Hudson, E, Vile, RG, Chester, JD & Parker, AL 2018, 'Ad5NULL-A20: A tropism-modified, avb6 integrin-selective oncolytic adenovirus for epithelial ovarian cancer therapies', Clinical Cancer Research, vol. 24, no. 17, pp. 4215-4224. https://doi.org/10.1158/1078-0432.CCR-18-1089
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 Geoffrey ; Chester, John D. ; Parker, Alan L. / Ad5NULL-A20 : A tropism-modified, avb6 integrin-selective oncolytic adenovirus for epithelial ovarian cancer therapies. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 17. pp. 4215-4224.
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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 avb6 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 avb6 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), avb3/5 integrins, and coagulation factor 10 (FX). Ad5NULL-A20 efficiently and selectively transduced avb6{\th} 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 avb6-overexpressing cancers and exciting platforms for tumor-selective overexpression of therapeutic anticancer modalities, including immune checkpoint inhibitors.",
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AU - Thompson, Jill M.

AU - Wongthida, Phonphimon

AU - Evgin, Laura

AU - Shim, Kevin G.

AU - Bradshaw, Angela

AU - Baker, Alexander T.

AU - Rizkallah, Pierre J.

AU - Jones, Rachel

AU - Hanna, Louise

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AU - Vile, Richard Geoffrey

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AU - Parker, Alan L.

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