Phase I Dose-Escalation Study of VB-111, an Antiangiogenic Virotherapy, in Patients with Advanced Solid Tumors

Brenner, Andrew; Cohen, Yaël; Breitbart, Eyal; Bangio, Livnat; Sarantopoulos, John; Giles, Francis J.; Borden, Ernest C.; Harats, Dror; Triozzi, Pierre L.

doi:10.1158/1078-0432.ccr-12-2079

Cited by 17 publications

(12 citation statements)

References 23 publications

(38 reference statements)

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“…VB-111 is a nonreplicating adenoviral vector (Ad-5, E1 deleted), containing a modified murine pre-proendothelin promoter (PPE-1-3X) and a Fas-chimera transgene (Fas and human TNF receptor 1). VB-111, which is undergoing early clinical evaluation, 36 infects angiogenic vasculature, leading to improved antitumor effects in xenograft and syngeneic cancer models. 37 Ad5ROBO4 is an E1- and E3-deleted adenovirus containing the endothelial human roundabout4 (ROBO4) enhancer/promoter, enabling the vector to target tumor endothelial cells.…”

Section: Oncolytic Viral Platforms Associated With Vascular Targetingmentioning

confidence: 99%

Targeting tumor vasculature through oncolytic virotherapy: recent advances

Bejarano¹,

Merchan²

2015

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The oncolytic virotherapy field has made significant advances in the last decade, with a rapidly increasing number of early- and late-stage clinical trials, some of them showing safety and promising therapeutic efficacy. Targeting tumor vasculature by oncolytic viruses (OVs) is an attractive strategy that offers several advantages over nontargeted viruses, including improved tumor viral entry, direct antivascular effects, and enhanced antitumor efficacy. Current understanding of the biological mechanisms of tumor neovascularization, novel vascular targets, and mechanisms of resistance has allowed the development of oncolytic viral vectors designed to target tumor neovessels. While some OVs (such as vaccinia and vesicular stomatitis virus) can intrinsically target tumor vasculature and induce vascular disruption, the majority of reported vascular-targeted viruses are the result of genetic manipulation of their viral genomes. Such strategies include transcriptional or transductional endothelial targeting, “armed” viruses able to downregulate angiogenic factors, or to express antiangiogenic molecules. The above strategies have shown preclinical safety and improved antitumor efficacy, either alone, or in combination with standard or targeted agents. This review focuses on the recent efforts toward the development of vascular-targeted OVs for cancer treatment and provides a translational/clinical perspective into the future development of new generation biological agents for human cancers.

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Section: Oncolytic Viral Platforms Associated With Vascular Targetingmentioning

confidence: 99%

Targeting tumor vasculature through oncolytic virotherapy: recent advances

Bejarano¹,

Merchan²

2015

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“…Similar to transductional peptides, the focus has been on enhancer/promoters activated in tumor endothelial cells. The two most intensively studied have been a human VEGR2 promoter fragment or a composite, modular, pre-proendothelin enhancer promoter (PPE-1-3x) [68, 69]. Both elements, but particularly the PPE-1-3x promoter, are induced by hypoxia commonly present within most tumor microenvironments.…”

Section: Discussionmentioning

confidence: 99%

“…Both elements, but particularly the PPE-1-3x promoter, are induced by hypoxia commonly present within most tumor microenvironments. This latter vector, now named VB-111, has been tested in Phase I trials [69]. In all cases, the goal of this work has been microvessel ablation.…”

Section: Discussionmentioning

confidence: 99%

A new model of multi-visceral and bone metastatic prostate cancer with perivascular niche targeting by a novel endothelial specific adenoviral vector

Kaliberov

Sohn

et al. 2017

Oncotarget

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While modern therapies for metastatic prostate cancer (PCa) have improved survival they are associated with an increasingly prevalent entity, aggressive variant PCa (AVPCa), lacking androgen receptor (AR) expression, enriched for cancer stem cells (CSCs), and evidencing epithelial-mesenchymal plasticity with a varying extent of neuroendocrine transdifferentiation. Parallel work revealed that endothelial cells (ECs) create a perivascular CSC niche mediated by juxtacrine and membrane tethered signaling. There is increasing interest in pharmacological metastatic niche targeting, however, targeted access has been impossible. Here, we discovered that the Gleason 7 derived, androgen receptor negative, IGR-CaP1 cell line possessed some but not all of the molecular features of AVPCa. Intracardiac injection into NOD/SCID/IL2Rg -/− (NSG) mice produced a completely penetrant bone, liver, adrenal, and brain metastatic phenotype; noninvasively and histologically detectable at 2 weeks, and necessitating sacrifice 4-5 weeks post injection. Bone metastases were osteoblastic, and osteolytic. IGR-CaP1 cells expressed the neuroendocrine marker synaptophysin, near equivalent levels of vimentin and e-cadherin, all of the EMT transcription factors, and activation of NOTCH and WNT pathways. In parallel, we created a new triple-targeted adenoviral vector containing a fiber knob RGD peptide, a hexon mutation, and an EC specific ROBO4 promoter (Ad.RGD.H5/3.ROBO4). This vector was expressed in metastatic microvessels tightly juxtaposed to IGR-CaP1 cells in bone and visceral niches. Thus, the combination of IGR-CaP1 cells and NSG mice produces a completely penetrant metastatic PCa model emulating end-stage human disease. In addition, the metastatic niche access provided by our novel Ad vector could be therapeutically leveraged for future disease control or cure.

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“…In 2013, Brenner et al [ 99 ] conducted a Phase I study considering the effectiveness of VB-111 in 33 patients with advanced solid tumors, including one patient with PTC. The patient with PTC responded well; CT scanning at 6 and 12 months following treatment with VB-111 demonstrated a more than 30% reduction in the diameter of the thyroid mass and some central necrosis and the patient had SD for 18 months.…”

Section: Immunotherapymentioning

confidence: 99%

Current Understanding of Nonsurgical Interventions for Refractory Differentiated Thyroid Cancer: a Systematic Review

et al. 2021

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Thyroid cancer incidence and related mortality is increasing year-on-year, and although treatment for early disease with surgery and radioiodine results in a 98% 5-year survival rate, recurrence and treatment refractory disease is evident in an unacceptable number of patients. Alternative treatment regimens have therefore been sought in the form of tyrosine kinase inhibitors, immunotherapy, vaccines, chimeric antigen receptor T-cell therapy and oncolytic viruses. The current review aims to consolidate knowledge and highlight the latest clinical trials using secondary therapies in thyroid cancer treatment, focusing on both in vitro and in vivo studies, which have investigated therapies other than radioiodine.

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Phase I Dose-Escalation Study of VB-111, an Antiangiogenic Virotherapy, in Patients with Advanced Solid Tumors

Cited by 17 publications

References 23 publications

Targeting tumor vasculature through oncolytic virotherapy: recent advances

Targeting tumor vasculature through oncolytic virotherapy: recent advances

A new model of multi-visceral and bone metastatic prostate cancer with perivascular niche targeting by a novel endothelial specific adenoviral vector

Current Understanding of Nonsurgical Interventions for Refractory Differentiated Thyroid Cancer: a Systematic Review

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