Targeting tumor vasculature through oncolytic virotherapy: recent advances

Abstract

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.

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

“…However, tumor cells adjacent to tumor vasculature, appeared to have cleared the virus infection to allow for regrowth of GFP-negative and RFP-positive tumor cells (indicated by the yellow dotted line). Consistent with previous reports [17], we observed some infected cells lining perfused blood vessels on day one post-infection. Contrary to the suggestion that this reflects direct oncolytic destruction of tumor vasculature, we observed that by day six post-infection these cells became GFP negative, but remained viable and supported vessel perfusion, indicating the ability of infected cells lining vasculature to clear virus in vivo ( Figure 1A,B).…”

“…Various oncolytic viruses (OVs) including oHSV can infect and lyse proliferating tumor cells and endothelial cells, resulting in reduced perfusion and anti-angiogenic effects [17,26,27]. However, we and others have uncovered that OV treatment induces secretion of VEGF and IL-8 in the tumor microenvironment (TME), thereby increasing angiogenesis in residual tumors after virus clearance [28][29][30].…”

Molecular Effects of Stromal-Selective Targeting by uPAR-Retargeted Oncolytic Virus in Breast Cancer

“…While it has been previously shown that tumor-stromal cross-talk modulates the sensitivity of cancer cells to oncolytic virues [49], ours is the first report, to our knowledge, to investigate the direct effect(s) of a stromal selective oncolytic viral vector on in vivo tumor progression. The current study differs from previous publications in that other reports have investigated the additional direct or indirect effects of targeted or armed oncolytic viruses (which primarily infect cancer cells) on other stromal components, especially the tumor vasculature [50]. …”

Simultaneous Tumor and Stroma Targeting by Oncolytic Viruses

“…Multiple approaches exist to target the tumor vasculature using genetically engineered OVs [86]. These approaches could be divided into OVs targeting the tumor vasculature by infecting the tumor VECs or inhibiting (pathways of) angiogenic cytokines and proteins specifically.…”