Increased efficacy of an interleukin-12-secreting herpes simplex virus in
a syngeneic intracranial murine glioma model

Hellums, Elizabeth K.; Markert, James M.; Parker, J.B.; He, Bin; Perbal, Bernard; Roizman, Bernard; Whitley, Richard J.; Langford, Catherine P.; Bharara, Suman; Gillespie, G. Yancey

doi:10.1215/s1152851705000074

Cited by 110 publications

(127 citation statements)

References 25 publications

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“…16 In this study, the feasibility of administering a replicationselective HSV-1 vector by CED into normal brain was therefore examined in detail. In spite of the large number of preclinical studies that have involved the direct intracranial administration of HSV-based vectors, 17,18,[20][21][22][23][24][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] remarkably this represents the first published study to evaluate the distribution properties of an HSV-1 vector using appropriate infusion parameters in both gray and white matter, as well as evaluation of strategies to improve vector distribution.…”

Section: Discussionmentioning

confidence: 99%

“…16 Clearly this has the potential to make the effective intracranial administration of HSV-1-based vectors unachievable. Nevertheless, in addition to the aforementioned clinical trials, [6][7][8][9] HSV vectors have been administered by stereotactic injection into normal mouse, [17][18][19] rat [20][21][22][23][24][25][26] and primate brains, [20][21][22][23][24][25][26][27][28] animal models of high-grade glioma, [29][30][31][32][33][34][35] mucopolysaccharidosis type VII, 36 GM2 gangliosidosis 37 and Parkinson's disease, [37][38][39] as well as being administered by CED into a glioma rat model. 40 In view of there being this large number of studies, it is surprising that to date no attempt has been made to systematically evaluate and optimize the delivery of these vectors directly into the brain.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

et al. 2011

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The direct intraparenchymal administration of oncolytic viral vectors by convection-enhanced delivery (CED) represents a promising new treatment strategy for malignant gliomas. However, there is no evidence to suggest that oncolytic viruses as large as herpes simplex virus-1 (HSV-1) can be administered by CED, as this has not been systematically examined in an animal model. In this study, the administration of a herpes simplex viral vector, HSV1, has been evaluated in detail in the gray and white matter of both rat and pig models, using high flow-rate infusions, co-infusing heparin or preinfusing the tissue with an isotonic albumin solution. Rat HSV-1 infusions at both slow (0.5 ml min À1 ) and high infusion rates (2.5 ml min À1 ) led to extensive tissue damage and negligible cell transduction. Co-infusion with heparin led to extensive hemorrhage. Preinfusion of tissue with an isotonic albumin solution facilitated widespread vector distribution and cell transduction in white matter only. Using this approach in pig brain led to widespread vector distribution with extensive transduction of astrocytes and activated microglia. In rat brain, enhanced green fluorescent protein expression peaked 48 h after vector administration and was associated with a vigorous immune response. These findings indicate that direct infusions of HSV-1-based viral vectors into the brain lead to minimal vector distribution, negligible cell transduction and extensive damage. Tissue preinfusion with an isotonic solution prior to vector administration represents an effective technique for achieving widespread HSV-1 distribution.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

et al. 2011

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“…33 With this respect, in some instances HSVs have been armed in order to achieve a better immune-mediated tumor killing. 34,35 Syngeneic models for gliomas have been developed in rats and mice. 36 The oncolytic virotherapy approaches undertaken with adenoviruses exploited mostly replication-deficient, locally delivered vectors carrying immunomodulatory molecules to boost the immune response and to recruit bone marrowderived dendritic cells, 37,38 clearly bypassing the issue of inhibition of viral replication by the immune system.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of HER2 retargeted herpes simplex virus as therapy for high-grade glioma in immunocompetent mice

et al. 2012

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Replication-competent oncolytic herpes simplex viruses (HSVs) are considered a promising therapeutic approach for treatment of high-grade gliomas (HGGs), which are usually resistant to all the available treatments. We previously demonstrated that R-LM113, a recombinant HSV-1 fully retargeted to the human epidermal growth factor receptor 2 (HER2), is safe and prolongs survival of immunodeficient NOD/SCID mice in an intracranial model of HGG. However, because the treatment is designed to be employed on immunocompetent patients, it is necessary to test whether the host immune system impairs the viral efficacy or triggers a potentially fatal reaction. Here we confirmed the safety of R-LM113 in the immunocompetent mouse strain BALB/c, where it does not trigger encephalitis when intracranially inoculated. Then, we set up a syngeneic HGG model expressing HER2 in adult BALB/c mice and evaluated R-LM113 therapeutic efficacy. We found that R-LM113 leads to a significant improvement in animal survival when administered at the time of tumor inoculation, as well as when injected into an already established tumor. This study suggests that the host immune defenses do not curtail the oncolytic antitumor activity of replication-competent HSV R-LM113, which results effective in counteracting tumor growth.

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“…In anticipation of clinical trials, numerous animal models of gliomas have demonstrated that both an oHSV deleted with both copies of γ 1 34.5 and oHSV that expressed foreign genes, particularly cytokines, can prolong survival in murine models of GBM. Indeed, second-generation oHSV that expresses either murine or human IL-12 has prolonged survival and enhanced the number of animals surviving compared with the first-generation virus, G207, a construct that has been studied in human trials (10,11).…”

Section: Approaches To Treatmentmentioning

confidence: 99%

Viral therapy of glioblastoma multiforme

Whitley

Markert

2013

Proc. Natl. Acad. Sci. U.S.A.

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Increased efficacy of an interleukin-12-secreting herpes simplex virus in a syngeneic intracranial murine glioma model

Cited by 110 publications

References 25 publications

Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

Evaluation and optimization of the administration of a selectively replicating herpes simplex viral vector to the brain by convection-enhanced delivery

Efficacy of HER2 retargeted herpes simplex virus as therapy for high-grade glioma in immunocompetent mice

Viral therapy of glioblastoma multiforme

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