Effective Treatment of Human Breast Tumor in a Mouse Xenograft Model with Herpes Simplex Virus Type 1 Specifying the NV1020 Genomic Deletion and the gBsyn3 Syncytial Mutation Enabling High Viral Replication and Spread in Breast Cancer Cells

Israyelyan, Anna; Melancon, Jeffrey M.; Lomax, Larry G.; Sehgal, Inder; Leuschner, Carola; Kearney, Michael T.; Chouljenko, Vladimir N.; Baghian, Abolghasem; Kousoulas, Konstantin G.

doi:10.1089/hum.2006.145

Cited by 21 publications

(31 citation statements)

References 67 publications

(79 reference statements)

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“…Thus, oncolytic HSV-1 may be effective both directly as a cancer killing agent and indirectly as an immunological enhancer, or in situ cancer vaccine (13,49). Previously, we reported that the novel fusogenic oncolytic herpesvirus OncSyn (OS) was effective at treating primary solid breast tumors in mice (25,26). Moreover, treatment of primary 4T1 tumors in syngeneic BALB/c mice with OS led to a substantial reduction in the formation of metastatic foci within multiple organs and in some cases eliminated lung metastasis, suggesting the development of effective antitumor immunity (43).…”

mentioning

confidence: 99%

Oncolytic Herpes Simplex Virus 1 Encoding 15-Prostaglandin Dehydrogenase Mitigates Immune Suppression and Reduces Ectopic Primary and Metastatic Breast Cancer in Mice

Walker¹,

Sehgal

Kousoulas³

2011

J Virol

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Oncolytic human herpes simplex viruses (HSV) have been genetically engineered to limit neurovirulence and the establishment of latency and reactivation and to replicate exclusively in cells with deficient apoptotic mechanisms (i.e., cancer cells) (5, 6, 37). These genetic changes are fundamental to the safety and efficacy of oncolytic herpesviruses but often result in rapid clearance of the virus by the host immune response, thus limiting its therapeutic potential. It is precisely the antiviral immune response, however, that is thought to help overcome tumor-induced immune suppression, allowing for antitumor immunity to develop. In this regard, HSV-1 infections within tumors may function as in situ vaccines, providing the necessary inflammatory signals that engage innate and adaptive immune responses to tumor antigens. Thus, oncolytic HSV-1 may be effective both directly as a cancer killing agent and indirectly as an immunological enhancer, or in situ cancer vaccine (13,49). Previously, we reported that the novel fusogenic oncolytic herpesvirus OncSyn (OS) was effective at treating primary solid breast tumors in mice (25,26). Moreover, treatment of primary 4T1 tumors in syngeneic BALB/c mice with OS led to a substantial reduction in the formation of metastatic foci within multiple organs and in some cases eliminated lung metastasis, suggesting the development of effective antitumor immunity (43).The HSV-1 vhs gene product encoded by the UL41 open reading frame (ORF) has multiple functions that are known to suppress antiviral immune responses. (i) vhs is an RNase that degrades viral and cellular mRNAs, limiting host and viral antigen production (3,32,33,45,48,51,56,59,61,65,75). (ii) UL41 (vhs) with ICP47 is known to inhibit major histocompatibility complex I (MHC-I) antigen presentation (59), while vhs alone has also been implicated in the reduction of MHC-II expression (69). (iii) vhs has been reported to suppress production of cytokines and chemokines and inactivate dendritic cells (7,59). In agreement with these reports, deletion of the vhs gene prevented HSV-1-mediated inactivation of antigen presentation by dendritic cells (DC) (54) and improved the immunogenicity of a candidate replication-defective HSV-1 vaccine strain (16,55). Furthermore, deletion of the vhs gene causes substantial reduction in neurovirulence (48, 60, 64).

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confidence: 99%

Oncolytic Herpes Simplex Virus 1 Encoding 15-Prostaglandin Dehydrogenase Mitigates Immune Suppression and Reduces Ectopic Primary and Metastatic Breast Cancer in Mice

Walker¹,

Sehgal

Kousoulas³

2011

J Virol

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“…Although the results of clinical trials have shown that these types of oncolytic HSV can safely be administered to humans, there is significant room for improvement in treatment efficacy, which is hampered, at least in part, by the reduced capacity of these viruses to replicate in tumor cells (69). Several groups of investigators have sought to take advantage of cell-cell fusion mechanisms to overcome the problem and have reported that syncytial mutations can enhance the potency of oncolytic HSV either or both in vitro and in vivo (52)(53)(54)(55). Since transductional targeting diminishes the dependence of oncolytic HSV on attenuating mutations for safety, our observations that gD retargeting does not interfere with syncytium formation by gB and gK syn mutants and that even a combination of syn mutations does not abolish the strict dependence of infection on the target receptor suggest that retargeted syn mutant HSV may offer oncolytic activity superior to that of the previous oncolytic syn mutant HSV strain.…”

Section: Discussionmentioning

confidence: 99%

“…A number of reports have demonstrated that the antitumor activity of various types of oncolytic HSV can be enhanced by syncytial mutations (52)(53)(54)(55). To determine if these effects are preserved in the context of our EGFR-retargeted HSV strain, we infected a panel of human pancreatic carcinoma cell lines (PANC-1, AsPC-1, PK-8, and BxPC-3) and examined the lateral spread of virus and cytocidal efficiency.…”

Section: Introduction Of Syncytial Mutations Into An Egfr-retargeted mentioning

confidence: 99%

Syncytial Mutations Do Not Impair the Specificity of Entry and Spread of a Glycoprotein D Receptor-Retargeted Herpes Simplex Virus

Okubo

Uchida

Wakata

et al. 2016

J Virol

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Membrane fusion, which is the key process for both initial cell entry and subsequent lateral spread of herpes simplex virus (HSV), requires the four envelope glycoproteins gB, gD, gH, and gL. Syncytial mutations, predominantly mapped to the gB and gK genes, confer hyperfusogenicity on HSV and cause multinucleated giant cells, termed syncytia. Here we asked whether interaction of gD with a cognate entry receptor remains indispensable for initiating membrane fusion of syncytial strains. To address this question, we took advantage of mutant viruses whose viral entry into cells relies on the uniquely specific interaction of an engineered gD with epidermal growth factor receptor (EGFR). We introduced selected syncytial mutations into gB and/or gK of the EGFR-retargeted HSV and found that these mutations, especially when combined, enabled formation of extensive syncytia by human cancer cell lines that express the target receptor; these syncytia were substantially larger than the plaques formed by the parental retargeted HSV strain. We assessed the EGFR dependence of entry and spread separately by using direct entry and infectious center assays, respectively, and we found that the syncytial mutations did not override the receptor specificity of the retargeted viruses at either stage. We discuss the implications of these results for the development of more effective targeted oncolytic HSV vectors. IMPORTANCEHerpes simplex virus (HSV) is investigated not only as a human pathogen but also as a promising agent for oncolytic virotherapy. We previously showed that both the initial entry and subsequent lateral spread of HSV can be retargeted to cells expressing tumor-associated antigens by single-chain antibodies fused to a receptor-binding-deficient envelope glycoprotein D (gD). Here we introduced syncytial mutations into the gB and/or gK gene of gD-retargeted HSVs to determine whether viral tropism remained dependent on the interaction of gD with the target receptor. Entry and spread profiles of the recombinant viruses indicated that gD retargeting does not abolish the hyperfusogenic activity of syncytial mutations and that these mutations do not eliminate the dependence of HSV entry and spread on a specific gD-receptor interaction. These observations suggest that syncytial mutations may be valuable for increasing the tumor-specific spreading of retargeted oncolytic HSV vectors. Herpes simplex virus 1 (HSV-1) is an important focus of research as a common human pathogen that often causes mucocutaneous lesions. In addition, HSV has recently shown promise as a tool for the development of novel therapeutic modalities against human cancers (1).Membrane fusion is the key process required for both initial entry of the virion into cells and subsequent lateral spread of HSV-1. HSV-1 entry depends on the interaction of gD with one of its cognate receptors: herpesvirus entry mediator (HVEM), nectin-1, or 3-O-sulfated heparan sulfate (3-OS-HS) (2-4). Receptor binding triggers a conformational change in gD that in turn activates...

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“…Alternatively, essential genes of the virus can be placed under the control of tissue-specific promoters, thus limiting their replication to specific tissues. [1][2][3] Finally, therapeutic strains in which the virus thymidine kinase gene remains unmodified will still be susceptible to antiviral drugs such as acyclovir. The combination of modified viruses with chemical agents to increase their potency in tumors shows promise for use in the treatment of human cancers.…”

Section: Discussionmentioning

confidence: 99%

“…Herpes simplex virus-1 (HSV-1) is a suitable candidate virus because of its large genome with many non-essential proteins, ease of manipulation, natural oncolytic properties and wide host tropism. [1][2][3] The removal of virulence genes enhances the safety of HSV-1 vectors against serious complications and/or reversion to wild type. [4][5][6] Some of these oncolytic HSV-1 viruses have been approved for clinical trials in breast cancer, 3,7 head and neck carcinoma, 8 glioma, 9 melanoma, 10 non-small-cell lung carcinoma 11 and metastases from colorectal cancer 12 (reviewed in Manservigi et al 13 ).…”

Section: Introductionmentioning

confidence: 99%

Effect of a caspase inhibitor, zVADfmk, on the inhibition of breast cancer cells by herpes simplex virus type 1

Wood

Shillitoe

2011

Cancer Gene Ther

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The oncolytic effects of herpes simplex virus-1 (HSV-1) are limited, possibly because of premature death of infected cells by apoptosis, which limits the amount of progeny virus that is produced. It has been proposed that inhibition of apoptosis in infected tumor cells would allow increased viral persistence, replication and therapeutic effect. To test this hypothesis, we infected monocyte chemoattractant factor-7 (MCF-7) and MDA-MB-231 breast cancer cells with HSV-1 strain 17 þ and 17Dg34.5 in the presence or absence of N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVADfmk), a pan-caspase inhibitor. At low doses of HSV-1 strain 17 þ and 17Dg34.5, the growth of MCF-7 cells was reduced to 37% or 42%, respectively, of uninfected cells. However, when cells were infected in the presence of zVADfmk, cell growth was further reduced to 24 and 33%. Similar results were seen in MDA-MB-231 cells. Cells treated with zVADfmk contained roughly 10 times more infectious viral particles than cells infected without zVADfmk, as shown by both plaque-forming and quantitative polymerase chain reaction assays. To model the situation within an infected tumor, supernatant fluids were collected from infected and non-infected cell cultures and then passed to non-infected cells. In the presence of zVADfmk, the cell growth inhibitory effect became stronger with repeated passages and was attributed to viral replication, because it could be prevented by anti-HSV antibody. These results suggest that caspases represent a novel target for drugs that increase the therapeutic efficacy of oncolytic herpes viruses against breast cancer.

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Effective Treatment of Human Breast Tumor in a Mouse Xenograft Model with Herpes Simplex Virus Type 1 Specifying the NV1020 Genomic Deletion and the gBsyn3 Syncytial Mutation Enabling High Viral Replication and Spread in Breast Cancer Cells

Cited by 21 publications

References 67 publications

Oncolytic Herpes Simplex Virus 1 Encoding 15-Prostaglandin Dehydrogenase Mitigates Immune Suppression and Reduces Ectopic Primary and Metastatic Breast Cancer in Mice

Oncolytic Herpes Simplex Virus 1 Encoding 15-Prostaglandin Dehydrogenase Mitigates Immune Suppression and Reduces Ectopic Primary and Metastatic Breast Cancer in Mice

Syncytial Mutations Do Not Impair the Specificity of Entry and Spread of a Glycoprotein D Receptor-Retargeted Herpes Simplex Virus

Effect of a caspase inhibitor, zVADfmk, on the inhibition of breast cancer cells by herpes simplex virus type 1

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