Replication-Competent Herpes Simplex Virus Vectors for Cancer Therapy

Rabkin, Samuel D.; Driever, Pablo Hernáiz

doi:10.1159/000061720

Cited by 11 publications

(5 citation statements)

References 331 publications

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“…Herpes simplex virus (HSV) has a broad cell tropism, and oncolytic viruses derived from parental HSV strains can lyse tumor cells of many different tissue origins 5. Nonetheless, tumor cells that are resistant HSV oncolysis are encountered from time to time and pose significant barriers to therapeutic outcomes.…”

Section: Introductionmentioning

confidence: 99%

Rapamycin enhances the activity of oncolytic herpes simplex virus against tumor cells that are resistant to virus replication

Tao

Rivera

et al. 2011

Intl Journal of Cancer

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Oncolytic herpes simplex virus (HSV) is currently in phase III clinical trials for development as a novel therapeutic agent against a broad range of human tumors. Although results have been promising, clinical outcome is likely to be compromised by intrinsic and acquired resistance to HSV replication, leading us to test agents that may overcome this obstacle. We found that, despite showing no effect on HSV replication in tumor cells fully permissive to the virus growth, the mTOR inhibitor rapamycin markedly increased the yield and dissemination of oncolytic HSVs in semipermissive tumor cells. Similar results were obtained in tumor-bearing mice. Co-administration of rapamycin with an HSV-derived oncolytic virus either blocked or reversed the growth of tumor xenografts established from semipermissive human tumor cells, while use of either agent alone produced only transient inhibitory effect. Together, our results suggest that rapamycin could be used to potentiate the activity of oncolytic HSVs against difficult-to-treat human tumors or perhaps to prevent the emergence of resistant tumor cells during virotherapy.Virotherapy has shown substantial promise as a new treatment modality for a broad range of human tumors. 1,2 The antitumor activity of an oncolytic virus derives mainly from its ability to replicate after it infects a tumor cell, with subsequent spread of the progeny virus to the nearby tumor cells. The resultant extent of tumor destruction often exceeds that achieved with many other types of cancer biotherapeutic agents. 3 Consequently, the ability of an oncolytic virus to replicate robustly in tumor cells is a key factor in securing a favorable outcome from virotherapy. 4 Herpes simplex virus (HSV) has a broad cell tropism, and oncolytic viruses derived from parental HSV strains can lyse tumor cells of many different tissue origins. 5 Nonetheless, tumor cells that are resistant to HSV oncolysis are encountered from time to time and pose significant barriers to therapeutic outcomes. Several strategies have been proposed to overcome the resistance of tumor cells to HSV. It has been reported, for example, that serial passage of an oncolytic HSV (a c34.5-deleted mutant) in resistant glioma cells can select for viral progeny that replicate more efficiently in the tumor cells and then show an enhanced antitumor effect against these resistant gliomas in vivo. 6 In our own studies, we showed that, although cyclophosphamide did not improve oncolytic HSV replication in the resistant Lewis lung carcinoma cells, its in vivo administration still enhanced the antitumor effect of the virotherapy. 7 Two groups have recently reported that rapamycin, an inhibitor of the mTOR (mammalian target of rapamycin) pathway, can increase the permissiveness of some resistant tumor cells to oncolytic myxoma virus or vesicular stomatitis virus (VSV). Stanford et al., for example, used rapamycin to pretreat human tumor cell lines that normally restrict myxoma virus replication and observed a striking increase in viral tropism and sprea...

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Section: Introductionmentioning

confidence: 99%

Rapamycin enhances the activity of oncolytic herpes simplex virus against tumor cells that are resistant to virus replication

Tao

Rivera

et al. 2011

Intl Journal of Cancer

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“…Additional oHSVs have been constructed and used in preclinical brain tumor models that involve mutations in genes other than γ 34.5 , such as ICP6 and US3 , or transcriptionally targeted vectors regulated by glioma-selective promoters, such as musashi 1 and nestin, or receptor-retargeted vectors using anti-HER2 (Table 1). In addition to GBM, other brain tumors are also attractive targets for oHSV, including: medulloblastoma, a major pediatric brain tumor of the cerebellum; meningioma, the most common primary intracranial tumor, arising from arachnoid cells, of which approximately 20% are atypical or malignant; and brain metastases, the most common type of brain tumor that have been increasing in frequency, with breast, lung and melanoma the most common [23]. …”

Section: Ohsvs For Brain Tumor Therapymentioning

confidence: 99%

Combinatorial strategies for oncolytic herpes simplex virus therapy of brain tumors

Kanai

Rabkin

2013

CNS Oncol.

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SUMMARY Oncolytic viruses, such as the oncolytic herpes simplex virus (oHSV), are an exciting new therapeutic strategy for cancer as they are replication competent in tumor cells but not normal cells. In order to engender herpes simplex virus with oncolytic activity and make it safe for clinical application, mutations are engineered into the virus. Glioblastoma multiforme (GBM) is the most common and deadly primary brain tumor in adults. Despite many advances in therapy, overall survival has not been substantially improved over the last several decades. A number of different oHSVs have been tested as monotherapy in early-phase clinical trials for GBM and have demonstrated safety and anecdotal evidence of efficacy. However, strategies to improve efficacy are likely to be necessary to successfully treat GBM. Cancer treatment usually involves multimodal approaches, so the standard of care for GBM includes surgery, radiotherapy and chemotherapy. In preclinical GBM models, combinations of oHSV with other types of therapy have exhibited markedly improved activity over individual treatments alone. In this review, we will discuss the various combination strategies that have been employed with oHSV, including chemotherapy, small-molecule inhibitors, antiangiogenic agents, radiotherapy and expression of therapeutic transgenes. Effective combinations, especially synergistic ones, are clinically important not just for improved efficacy but also to permit lower and less-toxic doses and potentially overcome resistance.

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“…2 -4 The pertinent features that allowed HSV-1 to be used as vectors for cancer therapy are still key to the continued development of newer and more efficient vectors. HSV-1 is attractive for cancer therapy because of the following characteristics: (a ) it infects a broad range of cell types and species; (b ) it is cytolytic by nature (i.e., the replicative life cycle of the virus results in host cell destruction ); (c ) the wellcharacterized large genome (152 kb ) contains many nonessential genes that can be replaced (up to 30 kb ) with multiple therapeutic transgenes; 5 ( d) a number of nonessential genes are associated with neurovirulence; 6,7 ( e) many antiherpetic drugs are available as a safeguard against unfavorable replication of the virus; 8 and ( f) the virus remains as an episome within the infected cell, even during latency, precluding insertional mutagenesis. 9 These are distinct advantages over other viral vectors, such as adenovirus, retrovirus, and vaccinia virus.…”

Section: Replication -Competent Oncolytic Herpes Simplex Virus ( Hsv mentioning

confidence: 99%

“…7 One potential drawback of g34.5 mutants is that they replicate less efficiently, with lower viral yields, as compared to wild -type virus. 32,33 Another attenuated HSV-1 mutant currently being studied extensively for cancer therapy is NV1020 (previously known as R7020 ), in which the joint region of the long ( L ) and short (S ) regions is deleted, including one copy of g34.5, UL24, and UL56.…”

Section: First -Generation Single -Mutant Hsv Vectorsmentioning

confidence: 99%

Oncolytic herpes simplex virus vectors for cancer virotherapy

2002

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Oncolytic herpes simplex virus type 1 (HSV-1) vectors are emerging as an effective and powerful therapeutic approach for cancer. Replication-competent HSV-1 vectors with mutations in genes that affect viral replication, neuropathogenicity, and immune evasiveness have been developed and tested for their safety and efficacy in a variety of mouse models. Evidence to-date following administration into the brain attests to their safety, an important observation in light of the neuropathogenicity of the virus. Phase I clinical traits of three vectors, G207, 1716, and NV1020, are either ongoing or completed, with no adverse events attributed to the virus. These and other HSV-1 vectors are effective against a myriad of solid tumors in mice, including glioma, melanoma, breast, prostate, colon, ovarian, and pancreatic cancer. Enhancement of activity was observed when HSV-1 vectors were used in combination with traditional therapies such as radiotherapy and chemotherapy, providing an attractive strategy to pursue in the clinic. Oncolytic HSV-1 vectors expressing ''suicide'' genes (thymidine kinase, cytosine deaminase, rat cytochrome P450) or immunostimulatory genes (IL-12, GM-CSF, etc.) have been constructed to maximize tumor destruction through multimodal therapeutic mechanisms. Further advances in virus delivery and tumor specificity should improve the likelihood for successful translation to the clinic.

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Replication-Competent Herpes Simplex Virus Vectors for Cancer Therapy

Cited by 11 publications

References 331 publications

Rapamycin enhances the activity of oncolytic herpes simplex virus against tumor cells that are resistant to virus replication

Rapamycin enhances the activity of oncolytic herpes simplex virus against tumor cells that are resistant to virus replication

Combinatorial strategies for oncolytic herpes simplex virus therapy of brain tumors

Oncolytic herpes simplex virus vectors for cancer virotherapy

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