ATN-224 enhances antitumor efficacy of oncolytic herpes virus against both local and metastatic head and neck squamous cell carcinoma

Yoo, Ji Young; Yu, Jun; Kaka, Azeem; Pan, Quintin; Kumar, Pawan; Kumar, Bhavna; Zhang, Jianying; Mazar, Andrew P.; Teknos, Theodoros N.; Kaur, Balveen; Old, Matthew

doi:10.1038/mto.2015.8

Cited by 10 publications

(14 citation statements)

References 31 publications

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“…Evaluation of changes in tumor microenvironment after oHSV therapy have uncovered changes in vascularization post therapy inciting several studies combining virotherapy with vascular disrupting agents and angiogenesis inhibitors (37). We have previously demonstrated increased anti-tumor effects when arming oHSV with Vstat120, a 120 kDa cleaved secreted fragment of BAI1, against a variety of preclinical cancer models, including glioblastoma, ovarian cancer, and head and neck cancer (6, 32, 38, 39). These effects had been heretofore attributed to the antiangiogenic effect of Vstat120 mediated by its conserved type I thrombospondin type I repeats (TSR), which bind to CD36 on endothelial cells and induce Fas-mediated apoptosis (12, 13).…”

Section: Discussionmentioning

confidence: 99%

BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection—Implications for Oncolytic Viral Therapy

Bolyard

Meisen

Banasavadi-Siddegowda

et al. 2017

Clinical Cancer Research

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Purpose Brain Angiogenesis Inhibitor (BAI1) facilitates phagocytosis, and bacterial pathogen clearance by macrophages; however, its role in viral infections is unknown. Here we examined the role of BAI1, and its N-terminal cleavage fragment (Vstat120) in antiviral macrophage responses to oncolytic herpes simplex virus (oHSV). Experimental Design Changes in infiltration and activation of monocytic and microglial cells after treatment of glioma-bearing mice brains with a control (rHSVQ1) or Vstat120-expressing (RAMBO) oHSV was analyzed using flow cytometry. Co-culture of infected glioma cells with macrophages or microglia was used to examine antiviral signaling. Cytokine array gene expression and ingenuity pathway analysis (IPA) helped evaluate changes in macrophage signaling in response to viral infection. TNFα blocking antibodies and macrophages derived from Bai1−/− mice were used. Results RAMBO treatment of mice reduced recruitment and activation of macrophages/microglia in mice with brain tumors, and showed increased virus replication compared to rHSVQ1. Cytokine gene expression array revealed that RAMBO significantly altered the macrophage inflammatory response to infected glioma cells via altered secretion of TNFα. Further we showed that BAI1 mediated macrophage TNFα induction in response to oHSV therapy. Intracranial inoculation of wild type/RAMBO virus in Bai1−/− or wild type non-tumor-bearing mice revealed the safety of this approach. Conclusions We have uncovered a new role for BAI1 in facilitating macrophage anti-viral responses. We show that arming oHSV with antiangiogenic Vstat120 also shields them from inflammatory macrophage antiviral response, without reducing safety.

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Section: Discussionmentioning

confidence: 99%

BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection—Implications for Oncolytic Viral Therapy

Bolyard

Meisen

Banasavadi-Siddegowda

et al. 2017

Clinical Cancer Research

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“…Female athymic nu/nu (Target Validation Shared Resource, The Ohio State University) or C57BL/6 male mice (Jackson Laboratories), aged 4–5-weeks, were injected subcutaneously with SCC-74A (1.5 × 10 7 ) or MTE (murine syngeneic) (1 × 10 6 ) cells in a volume of 100 μL into the rear flank, respectively. Mice were then recruited into studies and randomized into treatment groups as previously described 33 . For SCC-74A (human xenograft) studies, mice were treated with 2 × 10 9 PFU Reolysin on days 0 and 7 post-recruitment and SAHA (50 mg/kg) was administered via intraperitoneal (i.p.)…”

Section: Methodsmentioning

confidence: 99%

“…injection on days 1, 3, 5, 8, 10, and 12. Tissues were harvested at the indicated time points for ex vivo killing 38 or immune cell phenotypic assessment and for tumor H&E immunohistochemistry (when tumors reached ∼1,500 mm 3 ) 33 as described. Animals were observed daily and tumor volumes were obtained as previously described 33 .…”

Section: Methodsmentioning

confidence: 99%

“…Tissues were harvested at the indicated time points for ex vivo killing 38 or immune cell phenotypic assessment and for tumor H&E immunohistochemistry (when tumors reached ∼1,500 mm 3 ) 33 as described. Animals were observed daily and tumor volumes were obtained as previously described 33 . Mice were euthanized when the tumor burden reached ∼1,500 mm 3 , if there was a >20% body mass loss, or at the indicated time points according to animal care and usage guidelines.…”

Section: Methodsmentioning

confidence: 99%

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Reolysin and Histone Deacetylase Inhibition in the Treatment of Head and Neck Squamous Cell Carcinoma

Jaime-Ramirez

Caserta

et al. 2017

Molecular Therapy - Oncolytics

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Oncolytic viruses (OVs) are emerging as powerful anti-cancer agents and are currently being tested for their safety and efficacy in patients. Reovirus (Reolysin), a naturally occurring non-pathogenic, double-stranded RNA virus, has natural oncolytic activity and is being tested in phase I–III clinical trials in a variety of tumor types. With its recent US Food and Drug Administration (FDA) orphan drug designation for several tumor types, Reolysin is a potential therapeutic agent for various cancers, including head and neck squamous cell carcinomas (HNSCCs), which have a 5-year survival of ∼55%. Histone deacetylase inhibitors (HDACis) comprise a structurally diverse class of compounds with targeted anti-cancer effects. The first FDA-approved HDACi, vorinostat (suberoylanilide hydroxamic acid [SAHA]), is currently being tested in patients with head and neck cancer. Recent findings indicate that HDAC inhibition in myeloma cells results in the upregulation of the Reolysin entry receptor, junctional adhesion molecule 1 (JAM-1), facilitating reovirus infection and tumor cell killing both in vitro and in vivo. In this study, we tested the anti-tumor efficacy of HDAC inhibitors AR-42 or SAHA in conjunction with Reolysin in HNSCCs. While HDAC inhibition increased JAM-1 and reovirus entry, the impact of this combination therapy was tested on the development of anti-tumor immune responses.

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“…Rapid Antiangiogenesis Mediated By Oncolytic Virus (RAMBO) is a Vasculostatin-expressing oHSV [14]. In our previously studies, we showed that the RAMBO virus significantly enhance antitumor and anti-angiogenic efficacy in preclinical models of GBM, head and neck squamous cell carcinoma (SCC), and ovarian cancers through its ability to reduce angiogenesis [14][15][16]. Due to the prominent anti-angiogenic activity of RAMBO, we hypothesized that it would be also effective against highly vascularized malignant STSs.…”

Section: Introductionmentioning

confidence: 99%

Enhancing Antitumor Efficacy of Heavily Vascularized Tumors by RAMBO Virus through Decreased Tumor Endothelial Cell Activation

Nair

Khosla

Otani

et al. 2020

Cancers

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Vascularization is a common pathology for many solid tumors, and therefore anti-angiogenic strategies are being investigated as a therapeutic target for treatment. Numerous studies are also being conducted regarding the effects of oncolytic viruses, including Imlygic TM , an FDA approved oncolytic herpes simplex virus-1 (oHSV) for the treatment of highly vascularized tumors such as Kaposi sarcoma (NCT04065152), and brain tumors. To our knowledge, the effects of combining oncolytic HSV with angiogenesis inhibition on endothelial cell activation has not been previously described. Here, we tested the effects of Rapid Antiangiogenesis Mediated By Oncolytic Virus (RAMBO), an oHSV which expresses a potent anti-angiogenic gene Vasculostatin on endothelial cell activation in heavily vascularized solid tumors. oHSV treatment induces endothelial cell activation, which inhibits virus propagation and oncolysis in adjacent tumor cells in vitro. Consistently, this was also observed in intravital imaging of intracranial tumor-bearing mice in vivo where infected tumor endothelial cells could efficiently clear the virus without cell lysis. Quantitative real-time PCR (Q-PCR), leukocyte adhesion assay, and fluorescent microscopy imaging data, however, revealed that RAMBO virus significantly decreased expression of endothelial cell activation markers and leukocyte adhesion, which in turn increased virus replication and cytotoxicity in endothelial cells. In vivo RAMBO treatment of subcutaneously implanted sarcoma tumors significantly reduced tumor growth in mice bearing sarcoma compared to rHSVQ. In addition, histological analysis of RAMBO-treated tumor tissues revealed large areas of necrosis and a statistically significant reduction in microvessel density (MVD). This study provides strong preclinical evidence of the therapeutic benefit for the use of RAMBO virus as a treatment option for highly vascularized tumors.

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ATN-224 enhances antitumor efficacy of oncolytic herpes virus against both local and metastatic head and neck squamous cell carcinoma

Cited by 10 publications

References 31 publications

BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection—Implications for Oncolytic Viral Therapy

BAI1 Orchestrates Macrophage Inflammatory Response to HSV Infection—Implications for Oncolytic Viral Therapy

Reolysin and Histone Deacetylase Inhibition in the Treatment of Head and Neck Squamous Cell Carcinoma

Enhancing Antitumor Efficacy of Heavily Vascularized Tumors by RAMBO Virus through Decreased Tumor Endothelial Cell Activation

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