*4.3. Other Combination Therapies*

Along with the growing interest in OVT in the field of cancer treatment, many preclinical and clinical studies have suggested the use of OVs in combination with other common cancer therapies. OVT has been shown to potentiate the response to chemotherapy and radiotherapy, so that it could re-sensitize the chemo-/radio-resistant cells. Therefore, the combination of OVT with chemotherapy and radiotherapy is currently being evaluated in several clinical trials for chemo-resistant patients (Table 1). One of the shared mechanisms of OVT and chemo-/radiotherapy is ICD, in which a plethora of DAMPs is released, resulting in maximum induction of innate and adaptive immune responses. Hence, using OVT along with chemo-/radiotherapy could decrease the required doses of toxic agents and consequently lessen the adverse events of high dose treatments. Recombinant OVs can express enzymes such as cytosine deaminase, which converts the non-toxic prodrug 5-fuorocytosine (5-FC) into a toxic drug 5-fluorouracil (5-FU) in the tumor milieu [152]. Such local production of chemotherapeutic agents would decrease the systemic adverse events. GMOVs encoding the FCU1 gene can produce two enzymes, FCY1 and FUR1, that convert 5-FC to 5-FU and consequently 5-FU-monophosphate to target 5-FU-resistant tumors [152]. The tumor ECM prevents the access of therapeutic agents to the tumor cells, making the tumor resistant to chemotherapy [281]. Combination of ECM-degrading GMOVs with chemotherapy overrides the ECM-induced chemo-resistance observed in solid tumors [281]. Combination therapy of OVs and chemotherapy has been shown to exert synergistic antitumor activities via enhancing tumor cell killing capacity of chemotherapeutic agents, increasing virus proliferation in tumor cells, and invigorating oncolytic activities of OVs [282,283].

Besides conventional chemotherapy and radiotherapy, OVs could be administered in combination with targeted therapies [284]. Histone deacetylase inhibitors (HDIs) are recently entered the clinic as a promising treatment for cancers [285]. The companion of HDIs with OVT increases viral replication, upregulates the transgene expression (such as GM-CSF in T-VEC), enhances virus spread through the tumor cells, and augments oncolytic activities [286,287]. Moreover, HDIs induce antitumor immunity by inducing the expression of NK cell activating ligands and expression of TAAs, resulting NK cells and CTLs priming [286]. Co-administration of OVs with some protein kinase inhibitors such as MEK-1/2 and BRAF, and also inhibitors of some transcription factors like STAT-1 and NK-κB has been shown to enhance the oncolytic activities of OVs [288,289]. MEK/BRAF inhibitors do not affect viral replication. Instead, they enhance ER stress-induced apoptosis following OVT [288]. Interferon-stimulated genes (ISGs) are associated with resistance of tumors to chemotherapy, radiotherapy, and OVT. STAT-1 and NK-κB inhibitors diminish the expression of ISGs and thereby increase the cytotoxicity of OVs [289].
