**Malin Peter and Florian Kühnel \***

Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; peter.malin@mh-hannover.de

**\*** Correspondence: kuehnel.florian@mh-hannover.de; Tel.: +49-511-532-3995

Received: 9 October 2020; Accepted: 11 November 2020; Published: 13 November 2020

**Simple Summary:** Oncolytic adenoviruses are engineered to selectively replicate in and destroy cancer tissue. Moreover, these viruses are promising tools to restore antitumor immune response in cancer patients due to their high immunogenicity and the ability to interfere with the immunosuppressive tumor microenvironment. Due to these characteristics, oncolytic adenoviruses can activate tumors for already existing, systemic immunotherapies. The goal of this review is to provide an introduction into the common concepts of oncolytic adenoviruses, and to present their current status in clinical development. We also want to report in detail on strategies to optimize the immunoactivating properties of these agents for future application in multistage cancer immunotherapies.

**Abstract:** Tumor-selective replicating "oncolytic" viruses are novel and promising tools for immunotherapy of cancer. However, despite their first success in clinical trials, previous experience suggests that currently used oncolytic virus monotherapies will not be effective enough to achieve complete tumor responses and long-term cure in a broad spectrum of cancers. Nevertheless, there are reasonable arguments that suggest advanced oncolytic viruses will play an essential role as enablers of multi-stage immunotherapies including established systemic immunotherapies. Oncolytic adenoviruses (oAds) display several features to meet this therapeutic need. oAds potently lyse infected tumor cells and induce a strong immunogenic cell death associated with tumor inflammation and induction of antitumor immune responses. Furthermore, established and versatile platforms of oAds exist, which are well suited for the incorporation of heterologous genes to optimally exploit and amplify the immunostimulatory effect of viral oncolysis. A considerable spectrum of functional genes has already been integrated in oAds to optimize particular aspects of immune stimulation including antigen presentation, T cell priming, engagement of additional effector functions, and interference with immunosuppression. These advanced concepts have the potential to play a promising future role as enablers of multi-stage immunotherapies involving adoptive cell transfer and systemic immunotherapies.

**Keywords:** oncolytic adenovirus; cancer immunotherapy; multi-stage; immunostimulatory; arming
