Eradication of Established Intracranial Rat Gliomas by Transforming Growth Factor β Antisense Gene Therapy
Like human gliomas, the rat 9L gliosarcoma secretes the immunosuppressive transforming growth factor β (TGF-β ). Using the 9L model, we tested our hypothesis that genetic modification of glioma cells to block TGF-β expression may enhance their immunogenicity and make them more suitable for active tu...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1996-04, Vol.93 (7), p.2909-2914 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Fakhrai, Habib Dorigo, Oliver Shawler, Daniel L. Lin, Hong Mercola, Dan Black, Keith L. Royston, Ivor Sobol, Robert E. |
| description | Like human gliomas, the rat 9L gliosarcoma secretes the immunosuppressive transforming growth factor β (TGF-β ). Using the 9L model, we tested our hypothesis that genetic modification of glioma cells to block TGF-β expression may enhance their immunogenicity and make them more suitable for active tumor immunotherapy. Subcutaneous immunizations of tumor-bearing animals with 9L cells genetically modified to inhibit TGF-β expression with an antisense plasmid vector resulted in a significantly higher number of animals surviving for 12 weeks (11/11, 100%) compared to immunizations with control vector-modified 9L cells (2/15, 13%) or 9L cells transduced with an interleukin 2 retroviral vector (3/10, 30%) (P < 0.001 for both comparisons). Histologic evaluation of implantation sites 12 weeks after treatment revealed no evidence of residual tumor. In vitro tumor cytotoxicity assays with lymph node effector cells revealed a 3- to 4-fold increase in lytic activity for the animals immunized with TGF-β antisense-modified tumor cells compared to immunizations with control vector or interleukin 2 gene-modified tumor cells. These results indicate that inhibition of TGF-β expression significantly enhances tumor-cell immunogenicity and supports future clinical evaluation of TGF-β antisense gene therapy for TGF-β -expressing tumors. |
| doi_str_mv | 10.1073/pnas.93.7.2909 |
| format | Article |
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Using the 9L model, we tested our hypothesis that genetic modification of glioma cells to block TGF-β expression may enhance their immunogenicity and make them more suitable for active tumor immunotherapy. Subcutaneous immunizations of tumor-bearing animals with 9L cells genetically modified to inhibit TGF-β expression with an antisense plasmid vector resulted in a significantly higher number of animals surviving for 12 weeks (11/11, 100%) compared to immunizations with control vector-modified 9L cells (2/15, 13%) or 9L cells transduced with an interleukin 2 retroviral vector (3/10, 30%) (P < 0.001 for both comparisons). Histologic evaluation of implantation sites 12 weeks after treatment revealed no evidence of residual tumor. In vitro tumor cytotoxicity assays with lymph node effector cells revealed a 3- to 4-fold increase in lytic activity for the animals immunized with TGF-β antisense-modified tumor cells compared to immunizations with control vector or interleukin 2 gene-modified tumor cells. These results indicate that inhibition of TGF-β expression significantly enhances tumor-cell immunogenicity and supports future clinical evaluation of TGF-β antisense gene therapy for TGF-β -expressing tumors.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.93.7.2909</identifier><identifier>PMID: 8610141</identifier><language>eng</language><publisher>United States: National Academy of Sciences of the United States of America</publisher><subject>Animals ; B lymphocytes ; Brain Neoplasms - pathology ; Brain Neoplasms - therapy ; Cancer ; Cell lines ; Cells ; Cellular immunity ; Cytotoxicity, Immunologic ; DNA, Antisense - administration & dosage ; DNA, Antisense - therapeutic use ; Gene Expression - drug effects ; Gene therapy ; Genetic Therapy - methods ; Genetic Vectors ; Glioma ; Gliosarcoma - pathology ; Gliosarcoma - therapy ; Humans ; Immunity (Disease) ; Immunization ; Immunogenicity ; Immunotherapy ; Immunotherapy - methods ; Interleukin-2 - biosynthesis ; Lymphocytes ; Lymphocytes - immunology ; Natural killer cells ; Plasmids ; Rats ; Rats, Inbred F344 ; Retroviridae ; Rodents ; T lymphocytes ; Time Factors ; Transforming Growth Factor beta - biosynthesis ; Transforming Growth Factor beta - genetics ; Tumors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 1996-04, Vol.93 (7), p.2909-2914</ispartof><rights>Copyright 1996 National Academy of Sciences</rights><rights>Copyright National Academy of Sciences Apr 2, 1996</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c579t-4ed44e27f112a62c5d395697187f8f0e5930436dad90769fcad4fb5395b7a7b33</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/93/7.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/39087$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/39087$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27901,27902,53766,53768,57992,58225</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8610141$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fakhrai, Habib</creatorcontrib><creatorcontrib>Dorigo, Oliver</creatorcontrib><creatorcontrib>Shawler, Daniel L.</creatorcontrib><creatorcontrib>Lin, Hong</creatorcontrib><creatorcontrib>Mercola, Dan</creatorcontrib><creatorcontrib>Black, Keith L.</creatorcontrib><creatorcontrib>Royston, Ivor</creatorcontrib><creatorcontrib>Sobol, Robert E.</creatorcontrib><title>Eradication of Established Intracranial Rat Gliomas by Transforming Growth Factor β Antisense Gene Therapy</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Like human gliomas, the rat 9L gliosarcoma secretes the immunosuppressive transforming growth factor β (TGF-β ). Using the 9L model, we tested our hypothesis that genetic modification of glioma cells to block TGF-β expression may enhance their immunogenicity and make them more suitable for active tumor immunotherapy. Subcutaneous immunizations of tumor-bearing animals with 9L cells genetically modified to inhibit TGF-β expression with an antisense plasmid vector resulted in a significantly higher number of animals surviving for 12 weeks (11/11, 100%) compared to immunizations with control vector-modified 9L cells (2/15, 13%) or 9L cells transduced with an interleukin 2 retroviral vector (3/10, 30%) (P < 0.001 for both comparisons). Histologic evaluation of implantation sites 12 weeks after treatment revealed no evidence of residual tumor. In vitro tumor cytotoxicity assays with lymph node effector cells revealed a 3- to 4-fold increase in lytic activity for the animals immunized with TGF-β antisense-modified tumor cells compared to immunizations with control vector or interleukin 2 gene-modified tumor cells. These results indicate that inhibition of TGF-β expression significantly enhances tumor-cell immunogenicity and supports future clinical evaluation of TGF-β antisense gene therapy for TGF-β -expressing tumors.</description><subject>Animals</subject><subject>B lymphocytes</subject><subject>Brain Neoplasms - pathology</subject><subject>Brain Neoplasms - therapy</subject><subject>Cancer</subject><subject>Cell lines</subject><subject>Cells</subject><subject>Cellular immunity</subject><subject>Cytotoxicity, Immunologic</subject><subject>DNA, Antisense - administration & dosage</subject><subject>DNA, Antisense - therapeutic use</subject><subject>Gene Expression - drug effects</subject><subject>Gene therapy</subject><subject>Genetic Therapy - methods</subject><subject>Genetic Vectors</subject><subject>Glioma</subject><subject>Gliosarcoma - pathology</subject><subject>Gliosarcoma - therapy</subject><subject>Humans</subject><subject>Immunity (Disease)</subject><subject>Immunization</subject><subject>Immunogenicity</subject><subject>Immunotherapy</subject><subject>Immunotherapy - methods</subject><subject>Interleukin-2 - biosynthesis</subject><subject>Lymphocytes</subject><subject>Lymphocytes - immunology</subject><subject>Natural killer cells</subject><subject>Plasmids</subject><subject>Rats</subject><subject>Rats, Inbred F344</subject><subject>Retroviridae</subject><subject>Rodents</subject><subject>T lymphocytes</subject><subject>Time Factors</subject><subject>Transforming Growth Factor beta - biosynthesis</subject><subject>Transforming Growth Factor beta - genetics</subject><subject>Tumors</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUGL1DAYhoMo67h69SAIwcPeWr80adOAl2WZHRcWBBnPIW2TnYxtMiapOn_LH-JvsmXGYfSgp0De5w3flwehlwRyApy-3TkVc0FznhcCxCO0ICBIVjEBj9ECoOBZzQr2FD2LcQsAoqzhAl3UFQHCyAJ9XgbV2VYl6x32Bi9jUk1v40Z3-M6loNqgnFU9_qgSXvXWDyriZo_X03U0PgzWPeBV8N_SBt-qNvmAf_7A1y7ZqF3UeKWdxuuNDmq3f46eGNVH_eJ4XqJPt8v1zfvs_sPq7ub6PmtLLlLGdMeYLrghpFBV0ZYdFWUlOKm5qQ3oUlBgtOpUJ4BXwrSqY6YpJ6jhijeUXqJ3h3d3YzPortXzHr3cBTuosJdeWfln4uxGPvivkgpO5_rVsR78l1HHJAcbW933ymk_Rsn5NIuo4b8g4VCWvGAT-OYvcOvH4KY_kAUQCnVZkwnKD1AbfIxBm9PABOSsWs6qpaCSy1n1VHh9vuYJP7o9y-fe7_S8f_WvXJqx75P-nibw1QHcxsnviaQCak5_ARLBx14</recordid><startdate>19960402</startdate><enddate>19960402</enddate><creator>Fakhrai, Habib</creator><creator>Dorigo, Oliver</creator><creator>Shawler, Daniel L.</creator><creator>Lin, Hong</creator><creator>Mercola, Dan</creator><creator>Black, Keith L.</creator><creator>Royston, Ivor</creator><creator>Sobol, Robert E.</creator><general>National Academy of Sciences of the United States of America</general><general>National Acad Sciences</general><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7QO</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>19960402</creationdate><title>Eradication of Established Intracranial Rat Gliomas by Transforming Growth Factor β Antisense Gene Therapy</title><author>Fakhrai, Habib ; Dorigo, Oliver ; Shawler, Daniel L. ; Lin, Hong ; Mercola, Dan ; Black, Keith L. ; Royston, Ivor ; Sobol, Robert E.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c579t-4ed44e27f112a62c5d395697187f8f0e5930436dad90769fcad4fb5395b7a7b33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Animals</topic><topic>B lymphocytes</topic><topic>Brain Neoplasms - pathology</topic><topic>Brain Neoplasms - therapy</topic><topic>Cancer</topic><topic>Cell lines</topic><topic>Cells</topic><topic>Cellular immunity</topic><topic>Cytotoxicity, Immunologic</topic><topic>DNA, Antisense - administration & dosage</topic><topic>DNA, Antisense - therapeutic use</topic><topic>Gene Expression - drug effects</topic><topic>Gene therapy</topic><topic>Genetic Therapy - methods</topic><topic>Genetic Vectors</topic><topic>Glioma</topic><topic>Gliosarcoma - pathology</topic><topic>Gliosarcoma - therapy</topic><topic>Humans</topic><topic>Immunity (Disease)</topic><topic>Immunization</topic><topic>Immunogenicity</topic><topic>Immunotherapy</topic><topic>Immunotherapy - methods</topic><topic>Interleukin-2 - biosynthesis</topic><topic>Lymphocytes</topic><topic>Lymphocytes - immunology</topic><topic>Natural killer cells</topic><topic>Plasmids</topic><topic>Rats</topic><topic>Rats, Inbred F344</topic><topic>Retroviridae</topic><topic>Rodents</topic><topic>T lymphocytes</topic><topic>Time Factors</topic><topic>Transforming Growth Factor beta - biosynthesis</topic><topic>Transforming Growth Factor beta - genetics</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fakhrai, Habib</creatorcontrib><creatorcontrib>Dorigo, Oliver</creatorcontrib><creatorcontrib>Shawler, Daniel L.</creatorcontrib><creatorcontrib>Lin, Hong</creatorcontrib><creatorcontrib>Mercola, Dan</creatorcontrib><creatorcontrib>Black, Keith L.</creatorcontrib><creatorcontrib>Royston, Ivor</creatorcontrib><creatorcontrib>Sobol, Robert E.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>Biotechnology Research Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fakhrai, Habib</au><au>Dorigo, Oliver</au><au>Shawler, Daniel L.</au><au>Lin, Hong</au><au>Mercola, Dan</au><au>Black, Keith L.</au><au>Royston, Ivor</au><au>Sobol, Robert E.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Eradication of Established Intracranial Rat Gliomas by Transforming Growth Factor β Antisense Gene Therapy</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>1996-04-02</date><risdate>1996</risdate><volume>93</volume><issue>7</issue><spage>2909</spage><epage>2914</epage><pages>2909-2914</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>Like human gliomas, the rat 9L gliosarcoma secretes the immunosuppressive transforming growth factor β (TGF-β ). Using the 9L model, we tested our hypothesis that genetic modification of glioma cells to block TGF-β expression may enhance their immunogenicity and make them more suitable for active tumor immunotherapy. Subcutaneous immunizations of tumor-bearing animals with 9L cells genetically modified to inhibit TGF-β expression with an antisense plasmid vector resulted in a significantly higher number of animals surviving for 12 weeks (11/11, 100%) compared to immunizations with control vector-modified 9L cells (2/15, 13%) or 9L cells transduced with an interleukin 2 retroviral vector (3/10, 30%) (P < 0.001 for both comparisons). Histologic evaluation of implantation sites 12 weeks after treatment revealed no evidence of residual tumor. In vitro tumor cytotoxicity assays with lymph node effector cells revealed a 3- to 4-fold increase in lytic activity for the animals immunized with TGF-β antisense-modified tumor cells compared to immunizations with control vector or interleukin 2 gene-modified tumor cells. These results indicate that inhibition of TGF-β expression significantly enhances tumor-cell immunogenicity and supports future clinical evaluation of TGF-β antisense gene therapy for TGF-β -expressing tumors.</abstract><cop>United States</cop><pub>National Academy of Sciences of the United States of America</pub><pmid>8610141</pmid><doi>10.1073/pnas.93.7.2909</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 1996-04, Vol.93 (7), p.2909-2914 |
| issn | 0027-8424 1091-6490 |
| language | eng |
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| source | Jstor Complete Legacy; MEDLINE; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry |
| subjects | Animals B lymphocytes Brain Neoplasms - pathology Brain Neoplasms - therapy Cancer Cell lines Cells Cellular immunity Cytotoxicity, Immunologic DNA, Antisense - administration & dosage DNA, Antisense - therapeutic use Gene Expression - drug effects Gene therapy Genetic Therapy - methods Genetic Vectors Glioma Gliosarcoma - pathology Gliosarcoma - therapy Humans Immunity (Disease) Immunization Immunogenicity Immunotherapy Immunotherapy - methods Interleukin-2 - biosynthesis Lymphocytes Lymphocytes - immunology Natural killer cells Plasmids Rats Rats, Inbred F344 Retroviridae Rodents T lymphocytes Time Factors Transforming Growth Factor beta - biosynthesis Transforming Growth Factor beta - genetics Tumors |
| title | Eradication of Established Intracranial Rat Gliomas by Transforming Growth Factor β Antisense Gene Therapy |
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