Intravenous oncolytic vaccinia expressing transgenes for enhanced safety, inhibition of shedding, imaging, and systemic cancer immunotherapy

Oncolytic viruses are broad-spectrum cancer immunotherapies with multiple mechanisms of action that complement other therapeutics, but concerns remain regarding intravenous (i.v.) safety, overexpression of transgenes, environmental shedding, and lack of imaging in patients. Here we describe the engineering and evaluation of an i.v. oncolytic vaccinia virus (VV) therapeutic expressing a hyperactive and selective herpes simplex virus thymidine kinase (HSV-TK.007). In the presence of i.v. or topical ganciclovir (GCV), HSV-TK.007 acted to block VV replication either systemically or topically for control of skin lesions and shedding, respectively. HSV-TK.007 expression also enabled systemic positron emission tomography-computed tomography (PET-CT) imaging of tumor-specific virus replication <i>in vivo</i> with radiolabeled GCV. Finally, expression of an interleukin-2 variant (IL-2v) from the VV enhanced efficacy. In summary, the addition of HSV-TK.007 to an i.v. oncolytic VV enabled on-demand inhibition of systemic viral replication, skin lesions, environmental shedding, and systemic real-time non-invasive imaging of replication. A phase 1-2 clinical trial was initiated with this i.v. oncolytic VV expressing HSV-TK.007.