Adenovirus-mediated in vivo B7-1 gene transfer induces anti-tumor immunity against pre-established primary tumor and pulmonary metastasis of rat osteosarcoma.
We have previously reported that an osteosarcoma vaccine generated by ex vivo transfection of B7-1 cDNA induces protective as well as curative immunity against B7-1-negative parental osteosarcoma. Because establishment of human osteosarcoma cell lines, which is a prerequisite for ex vivo gene transfer, is rarely successful, we, in the present study, investigated the therapeutic efficacy of adenovirus-mediated in vivo B7-1 gene transfer to pre-established primary tumor as well as pulmonary metastasis of osteosarcoma. Adenovirus-mediated rat B7-1 gene transfer induced (a) expression of B7-1 molecules in osteosarcoma cells by both in vitro and in vivo infection procedures, (b) curative immunity against pre-established primary osteosarcoma and, subsequently, hosts gained protection against additional challenge of parental B7-1-negative osteosarcoma cells, (c) systemic immunity against pre-established pulmonary metastasis, and (d) activation of regional lymph node CD4(+) T cells, expansion of dendritic cells and natural killer cells and the secretion of interferon-gamma. These findings collectively support the therapeutic value of adenovirus-mediated in vivo gene transfer on osteosarcoma, which is of greater simplicity than cell-based B7-1 vaccine, and represent an attractive strategy for therapy of patients with metastatic osteosarcama who acquired resistance to current therapeutic protocols.
Tsuji
Hideki
H
Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan. gonchan@za2.so-net.ne.jp
Kawaguchi
Satoshi
S
Wada
Takuro
T
Nagoya
Satoshi
S
Inobe
Manabu
M
Yamashita
Toshihiko
T
Ishii
Seiichi
S
Uede
Toshimitsu
T
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D018122:B7-1 Antigen / Q000235:genetics* / Q000276:immunology; D001859:Bone Neoplasms / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D007111:Immunity, Cellular; D007694:Killer Cells, Natural / Q000276:immunology; D007763:Lac Operon / Q000235:genetics; D008175:Lung Neoplasms / Q000276:immunology* / Q000556:secondary / Q000821:virology; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D012516:Osteosarcoma / Q000276:immunology* / Q000556:secondary / Q000821:virology; D012313:RNA / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D018122:B7-1 Antigen; D012313:RNA