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Enhancing Antitumor Efficacy of Heavily Vascularized Tumors by RAMBO Virus through Decreased Tumor Endothelial Cell
Mitra Nair1, Maninder Khosla2, Yoshihiro Otani1
1Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Abstract:
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 ImlygicTM, 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.
Insights
Rapid Antiangiogenesis Mediated By Oncolytic Virus (RAMBO) decreases endothelial cell activation, enhancing oncolytic virus therapy for vascularized tumors. This novel approach shows significant tumor growth reduction and necrosis in preclinical models.
Area of Science:
- Oncology
- Virology
- Immunology
Background:
- Vascularization is a hallmark of many solid tumors, making anti-angiogenic strategies a key therapeutic focus.
- Oncolytic viruses (oHSV) are being explored for cancer treatment, with some approved for highly vascularized tumors.
- The combined effect of oHSV and angiogenesis inhibition on endothelial cell activation remains largely undescribed.
Purpose of the Study:
- To investigate the impact of a novel oncolytic herpes simplex virus-1 (oHSV) expressing Vasculostatin, termed RAMBO, on endothelial cell activation in vascularized solid tumors.
- To evaluate the efficacy of RAMBO in enhancing oncolytic virus therapy by modulating the tumor microenvironment.
Main Methods:
- Utilized quantitative real-time PCR (Q-PCR), leukocyte adhesion assays, and fluorescent microscopy to assess endothelial cell activation markers and leukocyte adhesion.
- Employed intravital imaging in intracranial tumor-bearing mice to observe virus propagation and endothelial cell response in vivo.
- Administered RAMBO treatment to mice with subcutaneously implanted sarcoma tumors and analyzed tumor growth, necrosis, and microvessel density (MVD).
Main Results:
- RAMBO treatment significantly decreased endothelial cell activation markers and leukocyte adhesion compared to control oHSV (rHSVQ).
- This reduction in activation enhanced virus replication and cytotoxicity within endothelial cells, leading to increased oncolysis.
- In vivo studies showed significantly reduced tumor growth, extensive necrosis, and a statistically significant decrease in MVD in RAMBO-treated tumors.
Conclusions:
- RAMBO, an oHSV engineered with Vasculostatin, effectively reduces endothelial cell activation and leukocyte adhesion in vascularized tumors.
- This modulation of the tumor microenvironment by RAMBO enhances oncolytic virus efficacy, leading to significant tumor growth inhibition and necrosis.
- RAMBO demonstrates strong preclinical therapeutic potential as a treatment for highly vascularized solid tumors.
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