HSV infection in wide ranges of cell populations results in degenerative change and death. HF10 is a ICI 182780 spontaneous mutant of HSV-1 strain HF that lacks neuroinvasiveness and is at least 10,000-fold less virulent than wild-type HSV-1 in mice. In several clinical studies of cancer patients, HF10 has been shown to have antitumor effects. In murine studies, HF10 packaged with a GM-CSF-expressing amplicon has been reported to exhibit more tumoricidal activity than intact HF10, supporting the hypothesis that HF10 exhibits maximal antitumor activity when used in combination with immunomodulators. Currently there is an ongoing clinical trial of a therapeutic anti-human GITR antibody. Thus, GITR targeting is an attractive candidate method for use in HF10 virotherapy as it encourages tumoricidal cytotoxic T lymphocyte activity and attenuates immune suppression. In this study, we examined the anti-tumor effects of i.t. treatment of established murine tumors with HF10 in combination with the GITR-specific agonistic monoclonal antibody DTA-1. Many studies involving oncolytic virus combined with systemic administration of cytotoxic agents have shown promising results in animal models. However, almost all of the studies have avoided the important issue of lymphocyte suppression caused by steroids as an antiemetic, implying the clinical inapplicability of such cytotoxic agents. Tumor therapy promises an era of safety in using noninvasive immunomodulatory agents including PD-1, CTLA4 and GITR-specific mAbs. Unfortunately, all of them have produced slight immune-related slight adverse events such as diarrhea, rashes or pruritis. In addition, systemic administration of immunomodulators can elicit serious autoimmune diseases. Therefore, local treatment of immunomodulators is a promising method for the future treatment of tumors. The use of blocking Abs for suppressing immune signals has shown clinical benefits in the treatment of solid tumors. Both PD-1 and CTLA-4, which are expressed on activated T cell surfaces, inhibit tumoricidal effector T cell responses by engagement via specific ligands that are expressed on various tumor cells. Interestingly, it has been reported that an antiCTLA-4 antibody augments tumoricidal effector T cells by downregulation of Treg cell functions, including ADCC-mediated depletion of Treg cells, which is similar to our GITRtargeting results. These reports indicate that the blockade of immune checkpoint molecules involves the activation of tumoricidal effector T cells by preventing interactions.