Concise Review: Targeting Cancer Stem Cells and Their Supporting Niche Using Oncolytic Viruses

Cancer stem cells (CSCs) have the capacity to self-renew and differentiate to give rise to heterogenous cancer cell lineages in solid tumors. These CSC populations are associated with metastasis, tumor relapse, and resistance to conventional anticancer therapies. Here, we focus on the use of oncolytic viruses (OVs) to target CSCs as well as the OV-driven interferon production in the tumor microenvironment (TME) that can repress CSC properties. We explore the ability of OVs to deliver combinations of immune-modulating therapeutic transgenes, such as immune checkpoint inhibitor antibodies. In particular, we highlight the advantages of virally encoded bi-specific T cell engagers (BiTEs) to not only target cell-surface markers on CSCs, but also tumor-associated antigens on contributing components of the surrounding TME and other cancer cells. We also highlight the crucial role of combination anticancer treatments, evidenced by synergy of OV-delivered BiTEs and chimeric-antigen receptor T cell therapy. Stem Cells 2019;37:716-723.