**Oncolytic Virus Encoding a Master Pro-Inflammatory Cytokine Interleukin 12 in Cancer Immunotherapy**

### **Hong-My Nguyen** †**, Kirsten Guz-Montgomery** † **and Dipongkor Saha \***

Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center School of Pharmacy, Abilene, TX 79601, USA; My.Nguyen@ttuhsc.edu (H.-M.N.);

Kirsten.Montgomery@ttuhsc.edu (K.G.-M.)

**\*** Correspondence: dipongkor.saha@ttuhsc.edu; Tel.: +1-325-696-0583

† These authors contributed equally to this work.

Received: 21 December 2019; Accepted: 29 January 2020; Published: 10 February 2020

**Abstract:** Oncolytic viruses (OVs) are genetically modified or naturally occurring viruses, which preferentially replicate in and kill cancer cells while sparing healthy cells, and induce anti-tumor immunity. OV-induced tumor immunity can be enhanced through viral expression of anti-tumor cytokines such as interleukin 12 (IL-12). IL-12 is a potent anti-cancer agen<sup>t</sup> that promotes T-helper 1 (Th1) di fferentiation, facilitates T-cell-mediated killing of cancer cells, and inhibits tumor angiogenesis. Despite success in preclinical models, systemic IL-12 therapy is associated with significant toxicity in humans. Therefore, to utilize the therapeutic potential of IL-12 in OV-based cancer therapy, 25 di fferent IL-12 expressing OVs (OV-IL12s) have been genetically engineered for local IL-12 production and tested preclinically in various cancer models. Among OV-IL12s, oncolytic herpes simplex virus encoding IL-12 (OHSV-IL12) is the furthest along in the clinic. IL-12 expression locally in the tumors avoids systemic toxicity while inducing an e fficient anti-tumor immunity and synergizes with anti-angiogenic drugs or immunomodulators without compromising safety. Despite the rapidly rising interest, there are no current reviews on OV-IL12s that exploit their potential e fficacy and safety to translate into human subjects. In this article, we will discuss safety, tumor-specificity, and anti-tumor immune/anti-angiogenic e ffects of OHSV-IL12 as mono- and combination-therapies. In addition to OHSV-IL12 viruses, we will also review other IL-12-expressing OVs and their application in cancer therapy.

**Keywords:** cancer immunotherapy; oncolytic virus; herpes simplex virus; immune checkpoint inhibitor; angiogenesis inhibitor
