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Bioreductive prodrug PR-104 improves the tumour distribution and titre of the nitroreductase-armed oncolytic adenovirus ONYX-411NTR leading to therapeutic benefit

Cancer Gene Therapy volume 29, pages 1021–1032 (2022)Cite this article

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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-411NTR 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-411NTR replication in vitro. In vivo, prodrug administration increased virus titre and improved virus distribution within tumour xenografts. Colonisation of tumours with high ONYX-411NTR titre resulted in NTR expression and prodrug activation. The combination of ONYX-411NTR 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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Fig. 1: Schematic of activation of 3,5-dinitrobenzamide mustards to cytotoxic metabolites by enzymatic reduction.
Fig. 2: NTR-dependent and hypoxia-dependent bystander effects of dinitrobenzamide mustards.
Fig. 3: Effect of acute prodrug exposure on titre of ONYX-411 in infected cells.
Fig. 4: Effect of prodrug on intratumour ONYX-411NTR replication.
Fig. 5: Combined efficacy of ONYX-411NTR with PR-104 against HCT116 xenografts.
Fig. 6: Intratumour activation of PR-104 by i.v. administered ONYX-411NTR.

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Funding

Funding support was received from the New Zealand Health Research Council, Cancer Society Auckland Northland, University of Auckland and Auckland Medical Research Foundation Doctoral Scholarships.

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Authors and Affiliations

  1. Auckland Cancer Society Research Centre, University of Auckland, Auckland, New Zealand

    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

  2. Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Auckland, New Zealand

    Dean C. Singleton, Alexandra M. Mowday, Amir Ashoorzadeh, Jeff B. Smaill, William R. Wilson & Adam V. Patterson

  3. Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

    Dean C. Singleton

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Contributions

DCS, WRW and AVP conceived and designed the experiments; DCS, AMM, CPG, SPS and SYB performed the experiments; DCS, WRW and AVP analysed the data; DL, AA and JBS contributed reagents/materials/analysis tools; DCS, AMM, CPG and AVP wrote the paper and JBS and WRW reviewed and edited the paper.

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Correspondence to Dean C. Singleton.

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Singleton, D.C., Mowday, A.M., Guise, C.P. et al. Bioreductive prodrug PR-104 improves the tumour distribution and titre of the nitroreductase-armed oncolytic adenovirus ONYX-411NTR leading to therapeutic benefit. Cancer Gene Ther 29, 1021–1032 (2022). https://doi.org/10.1038/s41417-021-00409-2

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