Ad5NULL-A20 – a precision virotherapy that efficiently and selectively targets αvβ6 positive cancers following intravenous administration


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Alan Parker1,James Davies1,Gareth Marlow1,Hanni Uusi-Kerttula1,Gillian Seaton1,Luke Piggott1,Richard Clarkson1,John Chester1
1Cardiff University, Cardiff, UK

Abstract

Background

Oncolytic virotherapies hold immense promise as anti-cancer agents due to their ability to self-amplify within tumours, lyse cells inducing immunogenic cell death, and express therapeutic modalities encoded within the viral genome. To develop a tumour selective adenovirus (Ad), we refined the Ad capsid to ablate all native means of infection, generating the basal vector, Ad5NULL. We incorporated a peptide, A20 (NAVPNLRGDLQVLAQKVART), that binds the tumour selective integrin, αvβ6, with high affinity, thus generating the “precision virotherapy” Ad5NULL-A20. Ad5NULL-A20 demonstrated ten-million-fold reduction in hepatic uptake following intravenous administration, and efficiently purged peritoneal metastases following intraperitoneal delivery in an in vivo model of ovarian cancer.

Method

We evaluated the ability of Ad5NULL-A20 to infect and kill αvβ6+ pancreatic and triple negative breast cancer (TNBC) cell lines in vitro, using reporter assays to quantify infectivity, and viability assays to monitor cell survival. We generated orthotopic, PDX models of TNBC and investigated the ability of Ad5NULL-A20 to home to tumours, quantifying viral genomes recovered from tumours and other organs 72 hours following intravascular delivery.

Results

We identified 7/9 pancreatic and 2/4 TNBC lines to be αvβ6+. Ad5NULL-A20 selectively transduced αvβ6+ cells, the oncolytic version killing cells in an αvβ6 dependent fashion. To evaluate systemic targeting of Ad5NULL-A20 to tumours, mice were orthotopically implanted with TNBC PDX tumours expressing low/medium/high levels of αvβ6. qPCR revealed remarkably improved tumour: liver ratios for Ad5NULL-A20 versus unmodified Ad5 in all tumour types tested, ranging from >50 fold in mice with αvβ6low PDX to >160 fold in αvβ6high PDX model. Viral genomes recovered from tumours increased as a function of αvβ6 positivity.

Conclusion

Ad5NULL-A20 represents an exciting platform with significant potential to treat αvβ6-expressing cancers either by intravenous or intraperitoneal approaches. Ad5NULL-A20 is well suited to arming with immunological transgenes for added efficacy, and for onward clinical translation.