title: Intratumoral interferon-alpha gene transfer enhances tumor immunity after allogeneic hematopoietic stem cell transplantation.
abstract: One of the major challenges in the treatment of solid cancers by allogenic hematopoietic stem cell transfer (alloHSCT) is the specific enhancement of antitumor immunity. Interferon (IFN) is a cytokine with pleiotropic biological functions including an immunomoduration, and our preclinical studies have shown that an intratumoral IFN-alpha gene transfer induced strong local tumor control and systemic tumor-specific immunity. In the present study, we examined whether the IFN-alpha gene transfer could enhance recognition of tumor-associated antigens by donor T cells and augment the antitumor activity of alloHSCT. First, when a mouse IFN-alpha adenovirus vector (Ad-mIFN) was injected into subcutaneous xenografts of syngeneic renal and colon cancer cells, tumor growth was significantly suppressed in a dose-dependent manner. A significant tumor cell death and infiltration of immune cells was recognized in the Ad-mIFN-injected tumors, and the dendritic cells isolated from the tumors showed a strong Th1-oriented response. The antitumor effect of Ad-mIFN was then examined in a murine model of minor histocompatibility antigen-mismatched alloHSCT. The intratumoral IFN-alpha gene transfer caused significant tumor suppression in the alloHSCT recipients, and this suppression was evident not only in the gene-transduced tumors but also in simultaneously inoculated distant tumors which did not receive the vector injection. A cytotoxicity assay showed specific tumor cell lysis by donor T cells responding to IFN-alpha. Graft-versus-host disease was not exacerbated serologically or clinically in the mice treated with IFN-alpha. This combination strategy deserves evaluation in future clinical trials for human solid cancers.
authors.affiliation: Section for Studies on Host-Immune Response, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo, Tokyo 104-0045, Japan.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Hara
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kobayashi
authors.forename: Kenta
authors.initials: K
authors.lastname: Narumi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kondoh
authors.forename: Kimiko
authors.initials: K
authors.lastname: Yoshida
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nishimoto
authors.forename: Masaki
authors.initials: M
authors.lastname: Ohashi
authors.forename: Eiji
authors.initials: E
authors.lastname: Higashihara
authors.forename: Shumpei
authors.initials: S
authors.lastname: Ohnami
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Kazunori
authors.initials: K
authors.lastname: Aoki
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology* / Q000628:therapy; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006086:Graft vs Host Disease / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D016898:Interferon-alpha / Q000235:genetics*; D007680:Kidney Neoplasms / Q000276:immunology* / Q000628:therapy; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008223:Lymphoma / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA
chemical_list: D016898:Interferon-alpha