Oncolytic viruses encoding bispecific T cell engagers: a blueprint for emerging immunovirotherapies

Bispecific T cell engagers (BiTEs) are an innovative class of immunotherapeutics that redirect T cells to tumor surface antigens. While efficacious against certain hematological malignancies, limited bioavailability and severe toxicities have so far hampered broader clinical application, especially against solid tumors. Another emerging cancer immunotherapy are oncolytic viruses (OVs) which selectively infect and replicate in malignant cells, thereby mediating tumor vaccination effects. These oncotropic viruses can serve as vectors for tumor-targeted immunomodulation and synergize with other immunotherapies. In this article, we discuss the use of OVs to overcome challenges in BiTE therapy. We review the current state of the field, covering published preclinical studies as well as ongoing clinical investigations. We systematically introduce OV-BiTE vector design and characteristics as well as evidence for immune-stimulating and anti-tumor effects. Moreover, we address additional combination regimens, including CAR T cells and immune checkpoint inhibitors, and further strategies to modulate the tumor microenvironment using OV-BiTEs. The inherent complexity of these novel therapeutics highlights the importance of translational research including correlative studies in early-phase clinical trials. More broadly, OV-BiTEs can serve as a blueprint for diverse OV-based cancer immunotherapies.