Targeting Tumor Vasculature With an Oncolytic Virus

Breitbach, Caroline J.; Silva, Naomi S. De; Falls, Theresa; Aladl, Usaf E.; Evgin, Laura; Paterson, Jennifer M; Sun, Yang; Roy, Dominic G.; Rintoul, Julia L.; Daneshmand, Manijeh; Parato, Kelley A.; Stanford, Marianne M.; Lichty, Brian D.; Fenster, Aaron; Kirn, David H.; Atkins, Harold L.; Bell, John C.

doi:10.1038/mt.2011.26

Cited by 152 publications

(129 citation statements)

References 21 publications

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“…Second, we previously made anecdotal observations with oncolytic vaccinia from individual mice and humans that were consistent with this hypothesis (20,21). Finally, with RNAbased oncolytic virus therapy, decreased tumor perfusion in mice (22,23) and infection of tumor-associated endothelial cells following anti-VEGFR therapy were reported (24). Nevertheless, definitive clinical and laboratory mechanistic data were lacking.…”

Section: Introductionmentioning

confidence: 90%

Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans

et al. 2013

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Efforts to selectively target and disrupt established tumor vasculature have largely failed to date. We hypothesized that a vaccinia virus engineered to target cells with activation of the ras/MAPK signaling pathway (JX-594) could specifically infect and express transgenes (hGM-CSF, b-galactosidase) in tumor-associated vascular endothelial cells in humans. Efficient replication and transgene expression in normal human endothelial cells in vitro required either VEGF or FGF-2 stimulation. Intravenous infusion in mice resulted in virus replication in tumor-associated endothelial cells, disruption of tumor blood flow, and hypoxia within 48 hours; massive tumor necrosis ensued within 5 days. Normal vessels were not affected. In patients treated with intravenous JX-594 in a phase I clinical trial, we showed dose-dependent endothelial cell infection and transgene expression in tumor biopsies of diverse histologies. Finally, patients with advanced hepatocellular carcinoma, a hypervascular and VEGF-rich tumor type, were treated with JX-594 on phase II clinical trials. JX-594 treatment caused disruption of tumor perfusion as early as 5 days in both VEGF receptor inhibitor-na€ ve and -refractory patients. Toxicities to normal blood vessels or to wound healing were not evident clinically or on MRI scans. This platform technology opens up the possibility of multifunctional engineered vaccinia products that selectively target and infect tumorassociated endothelial cells, as well as cancer cells, resulting in transgene expression, vasculature disruption, and tumor destruction in humans systemically. Cancer Res; 73(4); 1265-75. Ó2012 AACR.

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Section: Introductionmentioning

confidence: 90%

Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans

et al. 2013

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“…An additional bystander mechanism evoked by OVs is vascular collapse (20,29). Breitbach and colleagues showed that vascular endothelial cells in the outer rim of some tumors are abnormally susceptible to VSV infection.…”

Section: Ovs Induce Tumor-specific Vascular Shutdownmentioning

confidence: 99%

Molecular Pathways: Multimodal Cancer-Killing Mechanisms Employed by Oncolytic Vesiculoviruses

Mahoney

Stojdl

2013

Clinical Cancer Research

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Cancer is a heterogeneous disease that, for the most part, is not effectively managed with existing therapies. Oncolytic viruses are an attractive class of experimental cancer medicine because, unlike conventional chemotherapeutic and molecularly targeted drugs, they orchestrate tumor cell death in multiple ways simultaneously. In this review, we discuss the numerous cancer-killing "pathways" marshalled by oncolytic vesiculoviruses. From directly infecting and lysing malignant cells, to engaging the host's innate and adaptive anticancer immune responses, to inducing vascular collapse within a tumor, oncolytic vesiculovirus therapy commandeers a coordinated, multipronged assault on cancer that is curative in numerous preclinical models. And as our appreciation of these mechanisms has progressed, so has our capacity to engineer improved outcomes. Notably, efforts to polarize the host's immune system toward the tumor and away from the virus have been particularly effective in immunocompetent murine models, and hold tremendous therapeutic promise for human patients. With a first-in-man phase I trial recently initiated in the United States, the clinical significance of oncolytic vesiculorivus therapy, after nearly 15 years of development, may soon come into focus.

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“…Recruitment of neutrophils to the infected tumor beds was proposed to as the mechanism for the observation of blood flow shut down within the tumor following VSV therapy (12). Further investigation showed that VSV replication in the tumor neovasculature initiated an inflammatory reaction, which included neutrophil-dependent initiation of microclots within tumor blood vessels (13).…”

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confidence: 99%

Attenuated, Oncolytic, but Not Wild-Type Measles Virus Infection Has Pleiotropic Effects on Human Neutrophil Function

Zhang

Patel

Dey

et al. 2012

The Journal of Immunology

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We previously showed that neutrophils play a role in regression of human tumor xenografts in immunodeficient mice following oncolytic vaccine measles virus (MV-Vac) treatment. In this study, we sought, using normal human neutrophils, to identify potential neutrophil-mediated mechanisms for the attenuated MV-Vac induced effects seen in vivo, by comparison with those consequent on wild-type (WT-MV) infection. Both MV-Vac and WT-MV infected and replicated within neutrophils, despite lack of SLAM expression. In both cases, neutrophils survived longer ex vivo postinfection. Furthermore, MV-Vac (but not WT-MV) infection activated neutrophils and stimulated secretion of several specific antitumor cytokines (IL-8, TNF-α, MCP-1, and IFN-α) via induction of de novo RNA and protein synthesis. In addition, MV-Vac (but not WT-MV) infection caused TRAIL secretion in the absence of de novo synthesis by triggering release of prefabricated TRAIL, via a direct effect upon degranulation. The differences between the outcome of infection by MV-Vac and WT-MV were not entirely explained by differential infection and replication of the viruses within neutrophils. To our knowledge, this is the first demonstration of potential mechanisms of oncolytic activity of an attenuated MV as compared with its WT parent. Furthermore, our study suggests that neutrophils have an important role to play in the antitumor effects of oncolytic MV.

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Targeting Tumor Vasculature With an Oncolytic Virus

Cited by 152 publications

References 21 publications

Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans

Oncolytic Vaccinia Virus Disrupts Tumor-Associated Vasculature in Humans

Molecular Pathways: Multimodal Cancer-Killing Mechanisms Employed by Oncolytic Vesiculoviruses

Attenuated, Oncolytic, but Not Wild-Type Measles Virus Infection Has Pleiotropic Effects on Human Neutrophil Function

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