*5.2. OVs with Chemotherapeutic Agents—Future Prospects*

In the last decade, many preclinical models have demonstrated that chemotherapeutic agents and OVs could work synergistically [11]. There are two main approaches to setting this combination:


It is important to consider that even if chemotherapy and OVs could seem good partners, not all combinations have showed synergistic effects. In fact, the result depends on different factors including OVs strain, cancer type and the exact drug(s) used, as well as their dosing regimen and schedule [113].

In terms of the two standard-of-care chemotherapeutic agents for melanoma, temozolomide and dacarbazine, there are both in vitro and in vivo studies that explored combinations with various oncolytic vectors. Specifically, an in vitro/in vivo study that tested the combination of dacarbazine with ZD-55-IL18, an oncolytic adenovirus encoding for IL-18, showed that there is a synergy between these two agents, observed in the induction of apoptosis of tumor cells, and inhibition of angiogenesis and metastasis [113]. Another in vitro study conducted on melanoma cell lines treated with temozolomide (TMZ) and another oncolytic adenovirus (Ad5/3.2xTyr) reported that TMZ enhanced the OV's antitumor effect without altering the expression of CAR or other viral receptors on cancer cells, but rather by blocking the tumor cell's cycle in the S/G2 phase, providing a better intracellular environment for the viral replicative cycle to develop. This finding is consistent with the higher number of genome copies detected inside infected tumor cells [114].

By way of conclusion, we could say that the combinatorial approach based on chemotherapy and oncolytic viruses is promising, but like every other approach, it has to face some challenges to push researchers even further. It is clear that there are some incompatibilities between chemotherapy and OVs [114] which must be taken into account when designing new combinations:


We must consider all of these notions to reach a combination that can work effectively with a synergistic interaction.
