TY - JOUR
T1 - Ad5NULL-A20
T2 - A tropism-modified, avb6 integrin-selective oncolytic adenovirus for epithelial ovarian cancer therapies
AU - Uusi-Kerttula, Hanni
AU - Davies, James A.
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
AU - Hudson, Emma
AU - Vile, Richard G.
AU - Chester, John D.
AU - Parker, Alan L.
N1 - Funding 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.
Funding Information:
We are most grateful to patients at Velindre Cancer Centre, Cardiff, UK, who donated ascites samples. We would like to thank Mrs. Dawn Roberts for technical assistance, Dr. Richard Stanton for his expertise in AdZ recombineering, Dr. Alexander Greenshields-Watson for his assistance with homology modeling and structural biology, the team who maintain the YASARA energy minimization server, Dr. Edward Wang for his guidance in immunohistochem-istry, Dr. Lisa Spary and clinicians at Velindre Cancer Centre for access to clinical ascites samples, Mr. William Matchett for his help with the IVIS 200 software, and Prof. Gavin Wilkinson, Dr. Michael Barry, and Dr. John Marshall for insightful discussions. 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.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/9/1
Y1 - 2018/9/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-18-1089
DO - 10.1158/1078-0432.CCR-18-1089
M3 - Article
C2 - 29798908
AN - SCOPUS:85051140352
SN - 1078-0432
VL - 24
SP - 4215
EP - 4224
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -