title: Immuno-viral therapy of brain tumors by combination of viral therapy with cancer vaccination using a replication-conditional HSV.
abstract: Here we developed an effective therapeutic approach using a replication-conditional mutant of herpes simplex virus (HSV), G207, for the treatment of metastatic tumors in the immunologically privileged central nervous system. An experimental model of brain metastasis was developed using BALB/c mice that harbored both intracranial (i.c.) and subcutaneous (s.c.) mouse CT26 colon adenocarcinoma tumors. Intratumoral injections of G207 into s.c. tumors elicited cytotoxic T-cell responses not only to HSV but also to a tumor antigen; however, only a limited antitumor effect was observed on metastatic brain tumors. To improve this antitumor effect, G207 was also injected into the brain tumor. After intratumoral injections of G207 into both i.c. and s.c. CT26 tumors, a significant antitumor effect was observed in the metastatic brain tumors. This therapeutic efficacy was absent in athymic mice, indicating that the antitumor effect could be mediated by T cells. Cytotoxic T-cell responses to HSV and the tumor antigen were induced by injections of G207 into i.c. and s.c. CT26 tumors. These results suggest that HSV-infected brain tumors may be efficiently eliminated by the induced anti-HSV T cells as well as by antitumor T cells. Therefore, this strategy of immuno-viral therapy, involving direct viral oncolytic activities and inducing antitumor and antiviral immune responses, may be useful for the treatment of tumors in the immunologically privileged central nervous system.
authors.affiliation: Division of Cellular Signaling, Institute for Advanced Medical Research, Shinju-ku, Tokyo 160-8582, Japan. todam@sc.itc.keio.ac.jp
authors.forename: Masahiro
authors.initials: M
authors.lastname: Toda
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Iizuka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawase
authors.forename: Keiichi
authors.initials: K
authors.lastname: Uyemura
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawakami
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D019496:Cancer Vaccines / Q000627:therapeutic use*; D003602:Cytotoxicity, Immunologic; D005260:Female; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015552:Injections, Intralesional; D007276:Injections, Intraventricular; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D018139:Simplexvirus / Q000502:physiology*; D013154:Spleen / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured; D014611:Vaccination; D014765:Viral Vaccines / Q000627:therapeutic use*; D014779:Virus Replication / Q000235:genetics*
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D014765:Viral Vaccines