Preclinical Toxicology of rQNestin34.5v.2: An Oncolytic Herpes Virus with Transcriptional Regulation of the ICP34.5 Neurovirulence Gene

E Antonio Chiocca, Hiroshi Nakashima, Kazue Kasai, Soledad A Fernandez, Michael Oglesbee, E Antonio Chiocca, Hiroshi Nakashima, Kazue Kasai, Soledad A Fernandez, Michael Oglesbee

Abstract

rQNestin34.5v.2 is an oncolytic herpes simplex virus 1 (oHSV) that retains expression of the neurovirulent ICP34.5 gene under glioma-selective transcriptional regulation. To prepare an investigational new drug (IND) application, we performed toxicology and efficacy studies of rQNestin34.5v.2 in mice in the presence or absence of the immunomodulating drug cyclophosphamide (CPA). ICP34.5 allows HSV1 to survive interferon and improves viral replication by dephosphorylation of the eIF-2α translation factor. rQNestin34.5v.2 dephosphorylated eIF-2α in human glioma cells, but not in human normal cells, resulting in significantly higher cytotoxicity and viral replication in the former compared to the latter. In vivo toxicity of rQNestin34.5v.2 was compared with that of wild-type F strain in immunocompetent BALB/c mice and athymic mice by multiple routes of administration in the presence or absence of CPA. A likely no observed adverse effect level (NOAEL) dose for intracranial rQNestin34.5v.2 was estimated, justifying a phase 1 clinical trial in recurrent glioma patients (ClinicalTrials.gov: NCT03152318), after successful submission of an IND.

Keywords: ICP34.5; herpes simplex virus; nestin, oncolytic virus, toxicology, glioblastoma, brain tumor, preclinical study.

© 2020 The Authors.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Kaplan-Meier Survival Curves Comparison of survival curves for athymic mice with an orthotopic human glioma treated with PBS (group 5), 3.5 × 107 PFU of rQNestin34.5v.2 (group 6), or 3.5 × 107 PFU of rQNestin34.5v.2 with CPA pre-administration, 2 days before virus injection. Animals scheduled to undergo scheduled necropsy at day 4 or 31 are not included. In group 7, there were 10 mice that underwent scheduled necropsy at day 4 and 4 that underwent scheduled necropsy at day 31. One mouse was still alive at the study termination and underwent scheduled necropsy at this time (included in graph). For group 6, there were 10 mice that underwent scheduled necropsy at days 4 and 7 that underwent scheduled necropsy at day 31. Two mice were still alive at study termination and underwent scheduled necropsy at this time (included in graph). For group 5, there were 10 mice that underwent scheduled necropsy at day 4, but none was alive for the day 31 and thereafter scheduled necropsies. There was a statistically significant increase in survival of animals from group 6 and 7 when compared to those from group 5 (p < 0.0001, log-rank test).
Figure 2
Figure 2
Brain Histology and Immunohistochemistry for Mouse 684 H&E (A, D, and G), HSV IHC (B, E, and H), and CD45 IHC (C, F, I) for brain from mouse 684. (A)–(F) are from the frontal area of brain located 1.32 mm anterior to bregma and where the needle tract with a band of pannecrosis and microgliosis was observed, but this tract was not located near tumor (not shown here). (D)–(F) are high-power microphotographs of (A)–(C). (G)–(I) are from a more caudal area, located 1.62 posterior to bregma, where periventricular HSV and CD45-positive cells were seen. CC, corpus callosum; LV, lateral ventricle; LSI, lateral septal nucleus; Hi, hippocampus; CP, choroid plexus; 3V, 3rd ventricle; MHb, medial habenular nucleus.
Figure 3
Figure 3
Brain Histology and Immunohistochemistry for Mouse 758 (A) H&E-stained section of brain from mouse 758. Arrow points to needle inoculation site. Immediately past the needle tract is a tumor showing extensive necrosis that is attributed to rQNestin34.5v.2 injection. (B) HSV immunohistochemistry (IHC) reveals extensive tumor infection with extension of the infection toward the ventricle (arrow). (C) High-power microphotograph of HSV IHC, showing cells at the ependymal surface and subependymal region that are HSV antigen-positive. (D) CD45 IHC showing several inflammatory cells present along the ependyma. (E) IHC for nestin in reactive astrocytes adjacent to tumor. Arrow points to a mitotic astrocyte. (F) Ependyma showing mild, yet extensive, nestin immunohistochemical staining in the same areas where HSV and CD45 cells are observed.
Figure 4
Figure 4
Longitudinal Persistence of oHSV Genomes in Brain (A) qPCR for rQNestin34.5v.2 genomes in brains, 4, 31, and 61 days after injection into brains with tumors. (B) qPCR for rQNestin34.5v.2 genomes in brains, 4, 31, and 61 days after injection into brains with tumors, in mice pretreated with CPA.

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Source: PubMed

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