*5.3. OVs with Radiotherapy—Future Prospects*

Anticancer synergistic interaction of radiation and OVs therapy has solid backing in the literature, and the enhancement of viral replication due to radiotherapy has been reported in different in vitro and in vivo models such as lung cancer and pleural mesothelioma [115,116]. In melanoma, apart from the clear and demonstrated efficacy of both approaches as a monotherapy to kill cancer cells [32], the synergy is due to three other aspects:


Twigger et al. tried to combine an oncolytic reovirus with radiation therapy in a variety of melanoma cell lines, observing that the combination yielded a statistically significant enhancement of viral cytotoxicity without affecting reoviral replication rates, but with an increase in apoptosis of cancer cells [117]. In another preclinical study, Kyula et al. investigated the combination of an oncolytic *Vaccinia* virus and radiotherapy in BRAF-mutated, Ras-mutated and wild type melanoma cell lines. Results showed that in melanoma cells that carried V600D or V600E BRAF mutations there had been an increased apoptosis [42]. Also, the combination of reovirus and radiation has shown to increase the tumor growth delay of the melanoma xenografts in the treated animals, and significantly improve the overall survival rate compared to the treatment with either of the individual therapies [118]. Importantly, Ras mutation is one of the driver mutations for melanoma and is associated with radio-resistance [58]. However, some viruses like: reovirus, VSV and HSV have been able to selectively target the Ras mutated melanoma cells and mediate cell death [119]. Therefore, oncolytic vectors able to lyse the radiation-resistant melanoma cells can exhibit a complementary therapeutic effect to radiotherapy. There are many ongoing attempts to find the optimal way to combine these two strategies to maximize the antitumor effect preclinically. More investigations are needed to understand how to exploit this combination in the complex context of metastatic unresectable melanomas and their application in clinics.
