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

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 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.

The Effect of Herpes Simplex Virus-Type-1 (HSV-1) Oncolytic Immunotherapy on the Tumor Microenvironment

“…Unfortunately, not all cancer cells within a tumor mass undergo active replication [ 103 ]. In addition, the TME contains non-tumoral cells such as immune infiltrates, fibroblast, and endothelial cells, which have been shown to not support the replication of OVs designed according to the aforementioned principles [ 104 , 105 ]. More recent approaches to restrict HSV-1 OVs to cancer cells include receptor retargeting [ 106 ], use of specific promoters to express critical viral genes [ 107 ], transcriptional and translational regulation of essential viral gene expression [ 108 ], and incorporation of miRNA target sites into viral genes [ 109 ].…”

Homogeneity of antibody-drug conjugates critically impacts the therapeutic efficacy in brain tumors

“…Male NSG mice (6–8 weeks old) were implanted with GBM12-RFP cells (2 × 10 5 cells) stereotactically into the right hemisphere (2 mm lateral and 2.5 mm posterior to bregma, 1 mm depth) as previously described ( Nair et al, 2020 ). Thirteen days after tumor implantation, craniectomy was performed over the tumor-implanted area.…”

Replication and Spread of Oncolytic Herpes Simplex Virus in Solid Tumors

“…This results in a significant extension of survival compared with bevacizumab monotherapy. The combination also increases oHSV infection and replication [103]. Another strategy demonstrated that chelating copper (Cu) could augment the efficacy of oHSV infection and replication by preventing angiogenesis and increasing the serum stability of oHSVs [104] (Figure 3).…”