Oncolytic parvoviruses: from basic virology to clinical applications

Abstract

Accumulated evidence gathered over recent decades demonstrated that some members of the Parvoviridae family, in particular the rodent protoparvoviruses H-1PV, the minute virus of mice and LuIII have natural anticancer activity while being nonpathogenic to humans. These studies have laid the foundations for the launch of a first phase I/IIa clinical trial, in which the rat H-1 parvovirus is presently undergoing evaluation for its safety and first signs of efficacy in patients with glioblastoma multiforme. After a brief overview of the biology of parvoviruses, this review focuses on the studies which unraveled the antineoplastic properties of these agents and supported their clinical use as anticancer therapeutics. Furthermore, the development of novel parvovirus-based anticancer strategies with enhanced specificity and efficacy is discussed, in particular the development of second and third generation vectors and the combination of parvoviruses with other anticancer agents. Lastly, we address the key challenges that remain towards a more rational and efficient use of oncolytic parvoviruses in clinical settings, and discuss how a better understanding of the virus life-cycle and of the cellular factors involved in virus infection, replication and cytotoxicity may promote the further development of parvovirus-based anticancer therapies, open new prospects for treatment and hopefully improve clinical outcome.

Figure 1

Pros and cons of oncolytic virotherapy. Illustrated are the main advantages of oncolytic virotherapy and the major challenges that remain to be tackled in order to improve clinical outcome.

Figure 2

The oncolytic rat parvovirus H-1PV. A) A model of the icosahedral capsid is illustrated showing the 2, 3 and 5 fold axes of symmetry [28] B) The 5 kb single-stranded linear DNA genome has unique palindromic terminal sequences (Pal) that serve as self-priming origins of replication. Transcription is regulated by the P4 and P38 promoters, whose position is indicated by arrows. There are two transcription units coding for the non-structural (NS) and structural (VP) proteins, respectively.

Figure 3

Towards individualized parvovirus-based treatments. A better understanding of PV-host interaction with identification of key cellular factors playing a role in the PV-life cycle and in virus-mediated cytotoxicity may provide valuable hints for a more rational and efficient use of PV-based therapies in clinical settings. Predictive tests may identify patients with a molecular portrait that makes them more likely to benefit from virus treatment or targeted combination therapies.