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Development of genetically refined “precision virotherapies” suitable for systemic anti-cancer applications

A Parker(1)

1: Cardiff University School of Medicine

Adenoviruses represent attractive agents for translational applications from vaccines to oncolytics. As oncolytics, their ability to induce lysis and immunogenic cell death following infection of target cells is advantageous. Furthermore, they are amenable to genetic engineering, enabling therapeutic transgenes to be overexpressed from infected cells.

Most oncolytic adenoviruses that have undergone clinical translation rely on improved selectivity of replication inside tumour cells over healthy cells. This depletes the pool of therapeutic available for “on-target” activity due to virus uptake in “off-target” cells. Our lab has pioneered a different approach, studying how adenoviruses infect healthy cells naturally, and used these insights to guide the development of refined, tumour selective agents. This has been achieved by combining “detargeting” modifications the three major structural proteins to prevent native cell entry, coupled with the incorporation of effective targeting peptides into the capsid to enhance “on target” infection of cancer cells.

We developed an “Ad5NULL” platform which can be targeted to tumour specific receptors through appropriate engineering. Our lead agent, Ad5NULL-A20 targets carcinomas expressing αvβ6 integrin, a marker of tumour aggression, following systemic application in mouse models. Ad5NULL-A20 (Trocept) is undergoing IND enabling studies, with clinical trials of this agent expressing a full-length immune checkpoint inhibitor expected to commence in patients with αvβ6 positive carcinomas by the end of 2024.

The tropism of the Ad5NULL platform can be manipulated to target alternative tumour antigens enabling targeting of αvβ6 negative tumour types such as gliomas and thus represents a versatile “plug-and-play” system for targeted therapeutic applications.

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