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.
Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan. gonchan@za2.so-net.ne.jp
Hideki
H
Tsuji
Satoshi
S
Kawaguchi
Takuro
T
Wada
Satoshi
S
Nagoya
Manabu
M
Inobe
Toshihiko
T
Yamashita
Seiichi
S
Ishii
Toshimitsu
T
Uede
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