H-1 Parvovirus as a Cancer-Killing Agent: Past, Present, and Future

Abstract

The rat protoparvovirus H-1PV is nonpathogenic in humans, replicates preferentially in cancer cells, and has natural oncolytic and oncosuppressive activities. The virus is able to kill cancer cells by activating several cell death pathways. H-1PV-mediated cancer cell death is often immunogenic and triggers anticancer immune responses. The safety and tolerability of H-1PV treatment has been demonstrated in early clinical studies in glioma and pancreatic carcinoma patients. Virus treatment was associated with surrogate signs of efficacy including immune conversion of tumor microenvironment, effective virus distribution into the tumor bed even after systemic administration, and improved patient overall survival compared with historical control. However, monotherapeutic use of the virus was unable to eradicate tumors. Thus, further studies are needed to improve H-1PV’s anticancer profile. In this review, we describe H-1PV’s anticancer properties and discuss recent efforts to improve the efficacy of H-1PV and, thereby, the clinical outcome of H-1PV-based therapies.

Immune System Stimulation by Oncolytic Rodent Protoparvoviruses

“…As reviewed recently [1,2], rodent protoparvoviruses are endowed with oncolytic properties. The molecular basis of protoparvovirus cancer cell specificity and killing activity is the subject of another review in this special issue [3]. In some cancer animal models, this direct viral oncolytic effect is potent enough to fully eradicate infected tumors, correlating with virus spread and viral oncotoxic protein NS1 expression throughout the neoplastic tissue [4].…”

Oncolytic H-1 Parvovirus Enters Cancer Cells through Clathrin-Mediated Endocytosis

“…Their genomes encompass the non-structural (NS) and the viral particle (VP) transcriptional units, whose expressions are regulated by the P4 and P38 promoters, respectively. The NS transcriptional unit encodes the NS1 and NS2 proteins, whereas the VP transcriptional unit encodes the VP1 and VP2 capsid proteins and the small alternatively translated protein [ 4 ].…”

The Present Status of Immuno-Oncolytic Viruses in the Treatment of Pancreatic Cancer

“…The approach of genetically modifying wild-type virus to express immunomodulatory genes resulting in stimulation or suppression of the patient’s immune system results in an immunogenically “hot” environment around the tumor, which promotes regression of the malignant cell population [ 31 ]. OV expression of immunomodulatory genes and resultant malignant cell regression may occur through differing mechanisms dependent on the gene(s) expressed, such as direct cell lysis, disruption of tumor microenvironment vasculature or other, ultimately leading to destruction of cancer cells [ 32 ]. A representation of how OVs can potentially eliminate tumors is shown in Figure 1 .…”

“…In 1949, the Russian Far East Virus was observed to inhibit the growth of tumors transplanted into mice [ 35 ]. In 1960, opportunistic infection of the rat protoparvovirus, H-1PV, was shown in transplantable human tumors, subsequently H-1PV was directly assessed in preclinical models and demonstrated suppressive properties of tumors cell proliferation [ 32 ]. These and other such discoveries of the potential anticancer properties of virus and advancements in recombinant DNA technology led to the development of genetically modified forms of virus to leverage the natural properties of viral replication in host cells as a means to induce cancer cell death and/or other means of regressing tumor progression via deletion or insertion of specific genes of interest to recruit the patient’s antitumor immunity.…”

“…While H-1PV has been observed in human tumors, it does not naturally occur in humans, thus allowing for primary treatments to be less negatively impacted by the patient’s immune system clearance of the virus. This increases the duration of the therapeutic window for application as an OV as compared to other OVs endogenous in the human population [ 32 ]. As with other OVs, H-1PV, when used as combination therapy with gemcitabine, increased median length of survival in preclinical models [ 52 ].…”