Double-faceted mechanism of parvoviral oncosuppression

doi:10.1016/j.coviro.2015.03.008

Current Opinion in Virology

Volume 13, August 2015, Pages 17-24

https://doi.org/10.1016/j.coviro.2015.03.008 Get rights and content

Highlights

•
H-1PV propagation in human glioma cells can be improved through forced selection.
•
Arming of H-1PV vectors with immunostimulants enhances tumor vaccine effects.
•
H-1PV cooperates (in)directly with immune cells in achieving tumor suppression.
•
Post-translational modifications of the NS-1 protein regulate H-1PV oncolytic activity.
•
Gliomas from H-1PV-treated patients contain viral NS1 proteins and immune infiltrates.

The H-1 parvovirus (H-1PV) exerts oncosuppressive action that has two components: oncotoxicty and immunostimulation. While many human tumor cells, including conventional drug-resistant ones, can be killed by H-1PV, some fail to support progeny virus production, necessary for infection propagation in neoplastic tissues. This limitation can be overcome through forced selection of H-1PV variants capable of enhanced multiplication and spreading in human tumor cells. In the context of further developing H-1PV for use in cancer therapy, arming it with immunostimulatory CpG motifs under conditions preserving replication and oncolysis enhances its action as an anticancer vaccine adjuvant. A first clinical study of H-1PV treatment in glioma patients has yielded evidence of intratumoral synthesis of the viral oncotoxic protein NS1 and immune cell infiltration.

Graphical abstract

Introduction

Oncolytic parvoviruses belong to the species rodent protoparvovirus 1 and consist of an icosahedral protein capsid about 25 nm in diameter, containing a linear single-stranded DNA genome of approximately 5000 nucleotides. This genome comprises two transcription units, encoding nonstructural and capsid proteins, whose integrity is important for viral infectiousness [1]. The present review focuses on the oncolytic parvovirus H-1PV, whose natural host is the rat but which can replicate in and kill a number of tumor-derived human cells, while sparing their normal counterparts. As H-1PV also exerts tumor-suppressive action in various animal models (see [2, 3] for recent reviews), it is being assessed and developed as a potential tool for cancer therapy and/or prevention. Its antitumor action has two components: oncotoxicity and anticancer immunostimulation. Its adjuvant effect depends, at least in part, on the immunogenicity of viral oncolysates, and is instrumental in mediating virus-induced anticancer vaccination in animal models (reviewed in [4, 5, 6]). This review aims to illustrate the duality of H-1PV antitumor action and to discuss prospects for its optimization through virus adaptation, engineering, and/or combination with other agents.

Section snippets

Oncotoxic activity of rodent protoparvoviruses

Oncolytic parvoviruses induce molecular disturbances that jeopardize the survival of infected tumor cells. Besides exhausting cell metabolites as a result of their multiplication, they encode proteins that may participate in shutting down cell DNA replication and gene expression, by binding and withholding cellular factors controlling these processes [2]. Some parvoviral products, such as the 83-kDa multi-function nonstructural protein NS1, appear to alter target cell integrity by directly or

Immune mediation of H-1 parvovirus oncosuppression

There is growing evidence that the immune reactions triggered by non-pathogenic H-1PV depend largely on whether tumor tissues are present or not. Several in vitro studies have consistently shown that infection of human peripheral blood mononuclear cells (PBMCs) by H-1PV is not productive, although the first steps of viral replication do occur. More detailed analysis has identified B-cells, macrophages, and natural killer (NK) cells as the main immune cell subpopulations infected by H-1PV. In

Conclusion: clinical evidence of parvovirus oncolytic and immunomodulatory effects

In an immunocompetent rat model of advanced malignant glioma, stereotactic intratumoral injection of H-1PV caused progressive reduction of tumor size and changes in tumor morphology, resulting in complete remission in the majority of treated animals. Immunohistochemical analyses of tumor remnants at a regression stage corresponding to 30–70% of the initial tumor volume revealed the presence of the cytotoxic parvoviral nonstructural protein NS1 in the residual tumor masses, but not in the

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgments

We are indebted to members of the laboratory for contributing to animal immunodepletion and monitoring (Dr. Svitlana Grekova, Dr. Ute Koch and Manuel Fischer) and virus adaptation (Nadja Thomas). We wish to thank Mrs. Dagmar Anders for help with graphical artwork and Dr. Kathleen Broman for critical reading of the manuscript. The authors’ experimental work under review was supported by grants from Oryx GmbH and the German Research Council (DFG grant RA 1891/2-1).

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Citation Excerpt :
Two previous applications of H-1PV in humans revealed no virus-related pathogenic effects.18,19 The oncosuppressive activity of H-1PV was demonstrated in numerous preclinical studies in glioblastoma and other tumor models.20,21 In rats, H-1PV can cross the blood-brain barrier, causing intracranial tumor regression after intravenous injection.22
Oncolytic virotherapy may be a means of improving the dismal prognosis of malignant brain tumors. The rat H-1 parvovirus (H-1PV) suppresses tumors in preclinical glioma models, through both direct oncolysis and stimulation of anticancer immune responses. This was the basis of ParvOryx01, the first phase I/IIa clinical trial of an oncolytic parvovirus in recurrent glioblastoma patients. H-1PV (escalating dose) was administered via intratumoral or intravenous injection. Tumors were resected 9 days after treatment, and virus was re-administered around the resection cavity. Primary endpoints were safety and tolerability, virus distribution, and maximum tolerated dose (MTD). Progression-free and overall survival and levels of viral and immunological markers in the tumor and peripheral blood were also investigated. H-1PV treatment was safe and well tolerated, and no MTD was reached. The virus could cross the blood-brain/tumor barrier and spread widely through the tumor. It showed favorable pharmacokinetics, induced antibody formation in a dose-dependent manner, and triggered specific T cell responses. Markers of virus replication, microglia/macrophage activation, and cytotoxic T cell infiltration were detected in infected tumors, suggesting that H-1PV may trigger an immunogenic stimulus. Median survival was extended in comparison with recent meta-analyses. Altogether, ParvOryx01 results provide an impetus for further H-1PV clinical development.
Moving oncolytic viruses into the clinic: clinical-grade production, purification, and characterization of diverse oncolytic viruses
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Oncolytic viruses (OVs) are unique anticancer agents based on their pleotropic modes of action, which include, besides viral tumor cell lysis, activation of antitumor immunity. A panel of diverse viruses, often genetically engineered, has advanced to clinical investigation, including phase 3 studies. This diversity of virotherapeutics not only offers interesting opportunities for the implementation of different therapeutic regimens but also poses challenges for clinical translation. Thus, manufacturing processes and regulatory approval paths need to be established for each OV individually. This review provides an overview of clinical-grade manufacturing procedures for OVs using six virus families as examples, and key challenges are discussed individually. For example, different virus features with respect to particle size, presence/absence of an envelope, and host species imply specific requirements for measures to ensure sterility, for handling, and for determination of appropriate animal models for toxicity testing, respectively. On the other hand, optimization of serum-free culture conditions, increasing virus yields, development of scalable purification strategies, and formulations guaranteeing long-term stability are challenges common to several if not all OVs. In light of the recent marketing approval of the first OV in the Western world, strategies for further upscaling OV manufacturing and optimizing product characterization will receive increasing attention.
Oncolytic Rodent Protoparvoviruses Evade a TLR- and RLR-Independent Antiviral Response in Transformed Cells
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³: Present address: Experimental Neurosurgery, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany.

View full text

Double-faceted mechanism of parvoviral oncosuppression

Highlights

Graphical abstract

Introduction

Section snippets

Oncotoxic activity of rodent protoparvoviruses

Immune mediation of H-1 parvovirus oncosuppression

Conclusion: clinical evidence of parvovirus oncolytic and immunomodulatory effects

References and recommended reading

Acknowledgments

Virology

J Virol

Virology

J Virol

J Virol

Int J Cancer

PLoS One

Parvoviruses: small does not mean simple

Annu Rev Virol

Molecular pathways: rodent parvoviruses — mechanisms of oncolysis and prospects for clinical cancer treatment

Clin Cancer Res

Rommelaere J: Oncolytic parvoviruses: from basic virology to clinical applications

Virology J

Parvoviruses — tools to fine-tune anticancer immune responses

Oncoimmunology

Parvoviruses: the friendly anticancer immuno-modulator

Oncolytic virotherapy as emerging immunotherapeutic modality: potential of parvovirus H-1

Front Oncol

A viral adaptor protein modulating casein kinase II activity induces cytopathic effects in permissive cells

Proc Natl Acad Sci USA

Cytosolic activation of cathepsins mediates parvovirus H-1-induced killing of cisplatin and TRAIL-resistant glioma cells

J Virol

Vesicular transport of progeny parvovirus particles through ER and Golgi regulates maturation and cytolysis

PLoS Pathog

Transcriptional activation by the parvoviral nonstructural protein NS-1 is mediated via a direct interaction with Sp1

Mol Cell Biol

An Sp1-binding site and TATA element are sufficient to support full transactivation by proximally bound NS1 protein of minute virus of mice

Virology

In vivo accumulation of cyclin A and cellular replication factors in autonomous parvovirus minute virus of mice-associated replication bodies

J Virol

Parvovirus minute virus of mice induces a DNA damage response that facilitates viral replication

PLoS Pathog

Recruitment of DNA replication and damage response proteins to viral replication centers during infection with NS2 mutants of Minute Virus of Mice (MVM)

Virology

Induction of programmed cell death by parvovirus H-1 in U937 cells: connection with the tumor necrosis factor alpha signalling pathway

J Virol

Parvovirus H-1-induced cell death: influence of intracellular NAD consumption on the regulation of necrosis and apoptosis

Virus Res

The cytotoxicity of the autonomous parvovirus minute virus of mice nonstructural proteins in FR3T3 rat cells depends on oncogene expression

J Virol

Modulation of minute virus of mice cytotoxic activities through site-directed mutagenesis within the NS coding region

J Virol