**1. Introduction**

Oncolytic viruses (OV) preferably replicate in and lyse tumor cells, and thus leave, healthy tissue unharmed. This common feature is either intrinsic or a consequence of genetic engineering [1]. OVs were initially designed to enable effective tumor cell lysis and virus spreading thereby ensuring a reliable control of viral replication in normal cells. However, it has been recognized that OVs exert multiple antitumor functions including the induction of innate and adaptive immune responses against the tumor. Oncolytic adenoviruses (oAds) have been among the earliest OVs to enter clinical trials. Onyx-015, an E1B55k mutant adenovirus for selective replication in p53 dysfunctional tumor cells, has been intensively investigated [2]. Though tumor responses had been observed in

patients, particularly in combination with chemotherapy, the therapeutic efficacy did not meet the high expectations [3]. Nevertheless, these pioneering studies demonstrated that administration of oAds is well tolerated and safe. Additionally, lessons have been learned for the development of the next generation of viruses. Several advances in the fields of tumor immunotherapy have stimulated the interest in adenoviruses as oncolytic agents. First, there was the successful phase III study of the herpesvirus T-Vec and its subsequent approval by the U.S. food and drug administration (FDA), which delivered the final proof that OVs provide a clinical benefit for cancer patients [4]. There was also the growing perception that adaptive, tumor-directed immune responses are the essential therapeutic outcome of virotherapy [5]. A striking advance was the success of checkpoint inhibitors demonstrating that tumor immunotherapy even facilitates long-term cure [6]. However, the observation that the vast majority of cancer patients do not respond to these therapies opened up new future perspectives for the clinical application of OVs. The ability of oncolysis to induce tumor inflammation and to interfere with impaired immune functions in tumors suggests that OVs are promising agents to sensitize tumors for checkpoint inhibitors. Corresponding clinical studies are ongoing and are expected to deliver results soon [7]. Regarding the immunogenic properties of adenoviruses, oAds are presumably well qualified to meet this therapeutic need. Furthermore, oAds can be easily equipped with immunostimulatory transgenes to modulate the tumor microenvironment and to engage specific immune effector mechanisms. In this review, we want to give an overview on the currently existing platforms of oncolytic adenoviruses as well as the current state of their clinical development. We will report on current concepts of arming oAds with cytokines or alternative immune activators and will finally discuss the future prospects of oAds as an integrative part of multi-stage immunotherapies.
