Oncolytic viruses have proven their therapeutic potential against a variety of different tumor entities both in vitro and in vivo. Their ability to selectively infect and lyse tumor cells, while sparing healthy tissues, makes them favorable agents for tumor-specific treatment approaches. Particularly, the addition of virotherapeutics to already established chemotherapy protocols (so-called chemovirotherapy) is of major interest. Here we investigated the in vitro cytotoxic effect of the oncolytic vaccinia virus GLV-1h68 combined with dual chemotherapy with nab-paclitaxel plus gemcitabine in four human pancreatic adenocarcinoma cell lines (AsPc-1, BxPc-3, MIA-PaCa-2, and Panc-1). This chemovirotherapeutic protocol resulted in enhanced tumor cell killing in two tumor cell lines compared to the respective monotherapies. We were thereby able to show that the combination of oncolytic vaccinia virus GLV-1h68 with nab-paclitaxel and gemcitabine has great potential in the chemovirotherapeutic treatment of advanced pancreatic adenocarcinoma. However, the key to a successful combinatorial chemovirotherapeutic treatment seems to be a profound viral replication, as tumor cell lines that were non-responsive to the combination therapy exhibited a reduced viral replication in the presence of the chemotherapeutics. This finding is of special significance when aiming to achieve a virus-mediated induction of a profound and long-lasting antitumor immunity.

Oncolytic virotherapy has made significant progress in recent years, however, widespread approval of viro-therapeutics is still limited. Primarily, this is due to the fact that currently available viro-therapeutics are mostly tested in monotherapeutic clinical trials exclusively (ie, not in combination with other therapies) and so far have achieved only small and often clinically insignificant responses. Given that the pre-dominantly immuno-therapeutic mechanism of virothera-peutics is somewhat time-dependent and rapidly growing tumors therefore exhibit only minor chances of being captured in time, scenarios with combination partners are postulated to be more effective. Combinatory settings would help to achieve a rapid stabilization or even reduction of onset tumor masses while providing enough time (numerous months) for achieving immuno-(viro) therapeutic success. For this reason, combination strategies of virotherapy with highly geno-toxic regimens, such as chemotherapy, are of major interest. A number of clinical trials bringing the concepts of chemo-therapy and viro-therapy together have previously been undertaken, but optimal scheduling of chemo-viro-therapy (maximizing the anti-tumor effect while minimizing the risk of overlapping toxicity) still constitutes a major challenge. Therefore, an overview of published as well as ongoing Phase I-III trials should improve our understanding of current challenges and future developments in this field.