Treatment of intracranial glioma with in situ interferon-gamma and tumor necrosis factor-alpha gene transfer.
Interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha) are potent immunostimulatory cytokines with demonstrated tumoricidal effects in a variety of cancers. With the aim of investigating their ability to generate antitumor immune responses in malignant brain tumors, we describe the use of in situ adenoviral-mediated IFNgamma and TNFalpha gene transfer in glioma-bearing rodents. Survival was prolonged in mice treated with AdmIFNgamma or AdTNFalpha compared to AdLacZ- and saline-inoculated controls, and AdmIFNgamma- or AdTNFalpha-treated animals revealed significantly smaller tumors. These effects were accompanied by significant up-regulation of tumor MHC-I expression in AdmIFNgamma-inoculated animals, and of MHC-II in AdTNFalpha-treated tumors. Significantly enhanced intratumoral infiltration with CD4(+) and CD8(+) T cells was visible in animals treated with AdmIFNgamma, AdTNFalpha, or a combination of AdmIFNgamma and AdTNFalpha. In addition, AdTNFalpha therapy down-regulated the expression of endothelial Fas ligand, a cell membrane protein implicated as a contributor to immune privilege in cancer. These findings demonstrate the effectiveness of local IFNgamma and TNFalpha gene transfer as a treatment strategy for glioma and illustrate possible physiological pathways responsible for the therapeutic benefit observed.
Ehtesham
Moneeb
M
Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Samoto
Ken
K
Kabos
Peter
P
Acosta
Frank L
FL
Gutierrez
Mervin A R
MA
Black
Keith L
KL
Yu
John S
JS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018572:Disease-Free Survival; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005910:Glioma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000627:therapeutic use*; D001616:beta-Galactosidase / Q000235:genetics
D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D001616:beta-Galactosidase