Construction and Characterization of an Oncolytic HSV Vector Containing a Fusogenic Glycoprotein and Prodrug Activation for Enhanced Local Tumor Control

Simpson, Guy R.; Coffin, Robert S.

doi:10.1007/978-1-59745-561-9_29

Cited by 7 publications

(3 citation statements)

References 24 publications

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“…A range of transgene inserts have been evaluated, including suicide genes (Chase et al, 1998;Aghi et al, 1999;Nakamura et al, 2001;Guffey et al, 2007), or those expressing antiangiogenic (Liu et al, 2006;Goodwin et al, 2012;Yoo et al, 2012), apoptotic (Han et al, 2007;Prabhakar et al, 2010), fusogenic (Nakamori et al, 2004;Simpson et al, 2009;Takaoka et al, 2011), and immunomodulatory proteins (Andreansky et al, 1998;Liu et al, 2003;Parker et al, 2005;Walker et al, 2011). Our group has focused on oHSV that express immunostimulatory cytokines (Andreansky et al, 1998;Parker et al, 2000;Hellums et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the Safety and Biodistribution of M032, an Attenuated Herpes Simplex Virus Type 1 Expressing hIL-12, After Intracerebral Administration toAotusNonhuman Primates

Roth

Cassady

Cody

et al. 2014

Human Gene Therapy Clinical Development

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Herpes simplex virus type 1 (HSV-1) mutants lacking the c 1 34.5 neurovirulence loci are promising agents for treating malignant glioma. Arming oncolytic HSV-1 to express immunostimulatory genes may potentiate therapeutic efficacy. We have previously demonstrated improved preclinical efficacy, biodistribution, and safety of M002, a c 1 34.5-deleted HSV-1 engineered to express murine IL-12. Herein, we describe the safety and biodistribution of M032, a c 1 34.5-deleted HSV-1 virus that expresses human IL-12 after intracerebral administration to nonhuman primates, Aotus nancymae. Cohorts were administered vehicle, 10 6 , or 10 8 pfu of M032 on day 1 and subjected to detailed clinical observations performed serially over a 92-day trial. Animals were sacrificed on days 3, 31, and 91 for detailed histopathologic assessments of all organs and to isolate and quantify virus in all organs. With the possible exception of one animal euthanized on day 16, neither adverse clinical signs nor sex-or dose-related differences were attributed to M032. Elevated white blood cell and neutrophil counts were observed in virus-injected groups on day 3, but no other significant changes were noted in clinical chemistry or coagulation parameters. Minimal to mild inflammation and fibrosis detected, primarily in meningeal tissues, in M032-injected animals on days 3 and 31 had mostly resolved by day 91. The highest viral DNA levels were detected at the injection site and motor cortex on day 3 but decreased in central nervous system tissues over time. These data demonstrate the requisite safety of intracerebral M032 administration for consideration as a therapeutic for treating malignant brain tumors.

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Section: Introductionmentioning

confidence: 99%

Evaluation of the Safety and Biodistribution of M032, an Attenuated Herpes Simplex Virus Type 1 Expressing hIL-12, After Intracerebral Administration toAotusNonhuman Primates

Roth

Cassady

Cody

et al. 2014

Human Gene Therapy Clinical Development

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“…One such fusogenic virus is the recombinant HSV-GALV,116, 117, 118 which combines the oncolytic HSV backbone with the gibbon ape leukemia virus (GALV) fusion protein. Although GALV has poor oncolytic potential alone, the virus is hyperfusogenic, and insertion of its F protein into oncolytic HSV has been reported to generate a fusogenic construct with significantly increased oncolytic potential 119 .…”

Section: Main Textmentioning

confidence: 99%

Syncytia Formation in Oncolytic Virotherapy

Burton

Bartee

2019

Molecular Therapy - Oncolytics

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Oncolytic virotherapy uses replication-competent virus as a means of treating cancer. Whereas this field has shown great promise as a viable treatment method, the limited spread of these viruses throughout the tumor microenvironment remains a major challenge. To overcome this issue, researchers have begun looking at syncytia formation as a novel method of increasing viral spread. Several naturally occurring fusogenic viruses have been shown to possess strong oncolytic potential and have since been studied to gain insight into how this process benefits oncolytic virotherapy. Whereas these naturally fusogenic viruses have been beneficial, there are still challenges associated with their regular use. Because of this, engineered/recombinant fusogenic viruses have also been created that enhance nonfusogenic oncolytic viruses with the beneficial property of syncytia formation. The purpose of this review is to examine the existing body of literature on syncytia formation in oncolytics and offer direction for potential future studies.

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“…To this purpose, it has been recently demonstrated that incorporation of cell membrane fusion capability into an oncolytic HSV can significantly increase the antitumor potency of the virus [217-219]. These oncolytic HSVs were constructed by different methods: (i) screening for the syncytial phenotype after random mutation of a well-established oncolytic HSV (to obtain Fu-10); (ii) insertion of the gene encoding the hyperfusogenic membrane glycoprotein of gibbon ape leukemia virus (GALV.fus) into the genome of an oncolytic HSV (to generate Synco-2); (iii) incorporation of both of these two membrane fusion mechanisms into a single oncolytic HSV (to generate Synco-2D); and (iv) combined expression of GALV with a highly potent prodrug activation gene (yeast cytosine deaminase/uracil phosphoribosyl-transferase fusion [Fcy::Fur]) [220]. These vectors have been tested for their antitumor activity against liver, breast, ovarian and metastatic prostate cancers showing a significant increase in viral oncolysis; this may lead to an enhanced clinical performance, especially in the late stage cancer patients.…”

Section: Hsv-1 Based Vectors For Cancer Gene Therapymentioning

confidence: 99%

HSV Recombinant Vectors for Gene Therapy~!2009-12-17~!2010-13-31~!2010-06-17~!

Manservigi¹,

Argnani²,

Marconi³

2010

TOVJ

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Abstract:The very deep knowledge acquired on the genetics and molecular biology of herpes simplex virus (HSV), has allowed the development of potential replication-competent and replication-defective vectors for several applications in human healthcare. These include delivery and expression of human genes to cells of the nervous systems, selective destruction of cancer cells, prophylaxis against infection with HSV or other infectious diseases, and targeted infection to specific tissues or organs. Replication-defective recombinant vectors are non-toxic gene transfer tools that preserve most of the neurotropic features of wild type HSV-1, particularly the ability to express genes after having established latent infections, and are thus proficient candidates for therapeutic gene transfer settings in neurons. A replication-defective HSV vector for the treatment of pain has recently entered in phase 1 clinical trial. Replication-competent (oncolytic) vectors are becoming a suitable and powerful tool to eradicate brain tumours due to their ability to replicate and spread only within the tumour mass, and have reached phase II/III clinical trials in some cases. The progress in understanding the host immune response induced by the vector is also improving the use of HSV as a vaccine vector against both HSV infection and other pathogens. This review briefly summarizes the obstacle encountered in the delivery of HSV vectors and examines the various strategies developed or proposed to overcome such challenges.Keywords: HSV, viral vectors, oncolytic vectors, gene therapy, neurodegenerative disorders, cancer, targeting, vaccines. THE HERPES SIMPLEX VIRUS LIFE CYCLEHerpes simplex virus (HSV) is an enveloped, doublestranded (ds) DNA virus [1]. The mature virion consists of different components: an external envelope containing about 13 glycoproteins involved in different functions, among which the first steps of binding and entry into the host cell; an amorphous layer known as the tegument, containing some 20 different proteins with structural and regulatory roles; and an icosadeltahedral capsid containing a toroidal dsDNA. The HSV-1 genome consists of 152 kb of linear, dsDNA arranged as long and short unique segments (UL and US) flanked by inverted repeated sequences (TRL/IRL and IRS/TRS, respectively) (Fig. 1). The repeated regions of the viral genome contain two immediate-early (IE) genes [infected cell protein (ICP) 4 and ICP0], a late (L) gene (ICP34.5) and the latency associated transcripts (LAT) that are each present in two copies. Thus, the repeated region located between the long and short segments of the genome (the joint repeat region) contains a single copy of each gene. HSV genome encodes approximately 90 genes that can be classified as essential or nonessential based on their requirement for virus replication in tissue culture. Essential genes are required for virus growth such that viral mutants lacking these genes can only establish a lytic infection if the missing genes are supplied in trans by an engineered c...

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Construction and Characterization of an Oncolytic HSV Vector Containing a Fusogenic Glycoprotein and Prodrug Activation for Enhanced Local Tumor Control

Cited by 7 publications

References 24 publications

Evaluation of the Safety and Biodistribution of M032, an Attenuated Herpes Simplex Virus Type 1 Expressing hIL-12, After Intracerebral Administration toAotusNonhuman Primates

Evaluation of the Safety and Biodistribution of M032, an Attenuated Herpes Simplex Virus Type 1 Expressing hIL-12, After Intracerebral Administration toAotusNonhuman Primates

Syncytia Formation in Oncolytic Virotherapy

HSV Recombinant Vectors for Gene Therapy~!2009-12-17~!2010-13-31~!2010-06-17~!

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