Efficient systemic delivery of oncolytic viruses remains an unresolved issue and an obstacle to the success of oncolytic virotherapy. One of the main barriers that lead to decreased oncolytic viral delivery to tumor cells is the tumor stromal component. A potential strategy to circumvent this problem is to use a retargeted oncolytic virus that is able to target, and replicate in tumor stromal cells. The aim of this study is to evaluate the consequences of tumor stromal/vascular targeting by oncolytic measles virus via urokinase receptor (uPAR) as they relate to improved viral delivery and antitumor efficacy.
We rescued and characterized a novel dual targeting MV-un-muPA, which binds human cancer cells via CD46 and murine tissues via murine uPAR. This novel virus variant was generated as a tool to investigate the ability of a virus to target tumor stromal cells, especially tumor microvasculature (via murine uPAR) and deliver the infection to tumor cells (via CD46) in vivo. In vitro, MV-un-muPA infected and induced cytotoxicity to human or murine cancer cells in a species specific manner. Efficient MV-un-muPA replication was demonstrated in multiple human and murine cancer cells as well as murine fibroblasts in vitro. MV-un-muPA mediated viral transfer was demonstrated between murine endothelial or murine fibroblast to (RFP expressing) human cancer cells. To further validate the consequences of tumor stromal/vascular targeting by oncolytic measles virus via uPAR as they relate to improved viral delivery, the effects of MV-un-muPA vs a non-targeted MV virus (MV-GFP) were assessed in human breast (MDA-MD231) and colon (HT-29) cancer xenograft models. In these models, tumor cells express human CD46 and the host stroma expresses murine uPAR. Tumor bearing mice were treated with MV-GFP (targeting tumor cells via CD46), dual targeting virus MV-un-muPA (target tumor stroma via murine uPAR, and tumor cells via CD46) by intravenous administration (3 doses). Systemic administration of MV-un-muPA resulted in a significant delay in tumor progression as well as improved survival compared to mice treated with vehicle control or MV-GFP. Tumor based studies showed increased levels of viral RNA, tumor apoptosis, resulted in a significantly reduced stroma and the reduction of cancer associated fibroblasts and endothelial cells, in tumors treated with the dual targeted virus, compared to MV-GFP.
In conclusion, our results demonstrate for the first time that dual targeting of tumor stroma and tumor cells by MV-un-m-uPA enhance in vivo viral delivery and oncolytic virus antitumor efficacy in two in vivo models of cancer. This serves as clear proof that vascular/stromal targeting is an effective strategy to enhance viral delivery and antitumor effects and support future studies to further uncover the potential of stromal targeted oncolytic viruses.
Citation Format: Yuqi Jing, Valery Chavez, Natasha Karishma Khatwani, Jaime Merchan. Antitumor efficacy of a dual stromal and tumor targeted oncolytic measles virus in breast and colon cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5920.