*4.1. Immune-Checkpoint and Cell Therapy*

Despite all the benefits, OVT as monotherapy cannot have a dramatic effect on tumor suppression and, like other immunotherapy methods, is used as combination therapy. A common complementary treatment strategy for OVT is ICI [260]. The overexpression of various immune checkpoints in the TME suppresses the response of immune cells. OVT and ICI seem to have synergistic effects [114,260]. OVT facilitates the infiltration of immune cells into the TME, and ICIs prevent the suppression of infiltrated immune cells activity. OVT also improves ICI access to the TME by destroying ECM and tumor vessels [6]. Recently, the use of OVs expressing mini-antibody (minibody) and single-chain variable fragment (scFv) against checkpoints has been able to block checkpoints locally in the TME, with fewer AEs [261,262]. Many clinical trials are currently examining the combination of ICI and OVT, the results of which primarily suggest that in order to achieve a better outcome, ICI should be prescribed after the onset of OV responses [6,263]. OVT increases the effectiveness of TIL and CAR-T cell therapy. OVT can increase the access of TILs and CAR-T cells to the tumor by altering the tumor matrix and increasing the chemokines such as CCL5 [264]. The secretion of IL-15, TNF-α and IL-2 from OVs in the TME increase the in situ proliferation and activation of TILs and enhances tumor response to CAR-T cell therapy [265,266]. Bispecific T-cell engagers (BiTEs) are fusion proteins containing two scAbs against tumor antigens and T cell surface CD3 [267]. The use of BiTE-expressing OVs can bridge T/CAR-T cells to TAA-expressing cells in the TME [267]. Furthermore, concomitant use of TAA-specific mAbs with OVT can enhance the antitumor response. However, the small size of OVs genome has made it difficult to encode whole antibodies [268] Combination of OVT with DC vaccines also improves the efficacy of DC vaccines by altering the TME immunosuppressive conditions [269]. OVs could be utilized as tumor vaccines in order to enhance the immune responses against established tumors or even prevent tumor recurrence. The main function of such OV-based tumor vaccines is the recruitment of APCs, facilitating the phagocytosis of tumor cells by APCs, and promoting the APC maturation to induce appropriate antitumor immune responses [270–272].
