title: Activating systemic T-cell immunity against self tumor antigens to support oncolytic virotherapy with vesicular stomatitis virus.
abstract: We have shown that the antitumor activity of vesicular stomatitis virus (VSV) against B16ova tumors in C57BL/6 mice is predominantly due to innate antiviral immune effectors. We have also shown that the innate immune-activating properties of VSV can be harnessed to prime adaptive T-cell responses against a tumor-associated antigen (TAA) if the virus is engineered to express the cDNA of the antigen. Here, we show that the combination of VSV expressing OVA as a model tumor antigen, along with adoptive T-cell therapy targeted against the same antigen, is superior to either treatment alone and induces systemic antitumor activity. In addition, we extend our findings with the OVA model to the therapeutic use of VSV expressing hgp100, a self TAA against which tolerance is well established in C57BL/6 mice. In contrast to VSV-ova, T-cell responses raised by VSV-hgp100 were insufficient to improve therapy against B16ova tumors compared with VSV-GFP alone. However, in combination with adoptive transfer of gp100-specific pmel T cells, intratumoral VSV-hgp100 cured significantly more mice than either virus or T cells alone. Even in an aggressive model of metastatic disease, antitumor therapy was generated at levels similar to those observed in the VSV-ova/OT-I model in which a potently immunogenic, nonself TAA was targeted. Therefore, individual poorly effective virotherapies and T-cell therapies that target self TAA of low immunogenicity, which reflects the situation in patients, can be combined to generate very effective antitumor therapy.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Phonphimon
authors.initials: P
authors.lastname: Wongthida
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Diaz
authors.forename: Christine
authors.initials: C
authors.lastname: Pulido
authors.forename: Diana
authors.initials: D
authors.lastname: Rommelfanger
authors.forename: Feorillo
authors.initials: F
authors.lastname: Galivo
authors.forename: Karen
authors.initials: K
authors.lastname: Kaluza
authors.forename: Timothy
authors.initials: T
authors.lastname: Kottke
authors.forename: Jill
authors.initials: J
authors.lastname: Thompson
authors.forename: Alan
authors.initials: A
authors.lastname: Melcher
authors.forename: Richard
authors.initials: R
authors.lastname: Vile
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D003131:Combined Modality Therapy; D007113:Immunity, Innate; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050130:Oncolytic Virotherapy; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D014407:Tumor Cells, Cultured; D014721:Vesicular stomatitis Indiana virus / Q000276:immunology / Q000502:physiology*; D014779:Virus Replication; D058951:gp100 Melanoma Antigen / Q000235:genetics / Q000276:immunology*
chemical_list: D058951:gp100 Melanoma Antigen