The central nervous system (CNS) has been considered an immunologically privileged site; however, recent evidence suggests that activated T cells cross the intact blood-brain barrier and that a series of immunological events is initiated when T cells recognize CNS antigens. Therefore, brain tumors might be selectively eliminated by T cells activated with antigens specific for the tumors. Using a conditionally replicating herpes simplex virus-1 (HSV-1) mutant, G207, we developed a novel therapeutic approach for metastatic brain tumors that combines viral therapy with immunotherapy. G207 replicates selectively within tumor cells and causes tumor cell destruction without local or systemic toxicity, because its replication in normal cells is highly attenuated. Furthermore, the inoculation of tumors outside the CNS with G207 induces systemic immune responses not only to HSV but also to tumor antigens. In our strategy, in which both the metastatic brain tumor and the primary tumor outside the CNS are inoculated with G207, the HSV-infected brain tumor can be eliminated by the combined effects of the direct oncolysis and the induced anti-HSV and antitumor T cells. Recently, the safety of directly inoculating the human brain with G207 has been shown. These results indicate that our therapeutic approach using G207 may hold promise for the treatment of metastatic brain tumors.
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