Bioreductive Prodrug PR-104 Improves the Tumour Distribution and Titre of the Nitroreductase-armed Oncolytic Adenovirus ONYX-411 Leading to Therapeutic Benefit

Overview

Journal Cancer Gene Ther

Specialties Genetics
Oncology
Pharmacology

Date 2021 Nov 27

PMID 34837065

Citations 2

Authors

Dean C Singleton

Alexandra M Mowday

Chris P Guise

Sophie P Syddall

Sally Y Bai

Dan Li

Amir Ashoorzadeh

Jeff B Smaill

William R Wilson

Adam V Patterson

Affiliations

Soon will be listed here.

Abstract

Advances in the field of cancer immunotherapy have stimulated renewed interest in adenoviruses as oncolytic agents. Clinical experience has shown that oncolytic adenoviruses are safe and well tolerated but possess modest single-agent activity. One approach to improve the potency of oncolytic viruses is to utilise their tumour selectivity to deliver genes encoding prodrug-activating enzymes. These enzymes can convert prodrugs into cytotoxic species within the tumour; however, these cytotoxins can interfere with viral replication and limit utility. In this work, we evaluated the activity of a nitroreductase (NTR)-armed oncolytic adenovirus ONYX-411 in combination with the clinically tested bioreductive prodrug PR-104. Both NTR-expressing cells in vitro and xenografts containing a minor population of NTR-expressing cells were highly sensitive to PR-104. Pharmacologically relevant prodrug exposures did not interfere with ONYX-411 replication in vitro. In vivo, prodrug administration increased virus titre and improved virus distribution within tumour xenografts. Colonisation of tumours with high ONYX-411 titre resulted in NTR expression and prodrug activation. The combination of ONYX-411 with PR-104 was efficacious against HCT116 xenografts, whilst neither prodrug nor virus were active as single agents. This work highlights the potential for future clinical development of NTR-armed oncolytic viruses in combination with bioreductive prodrugs.

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