Recombinant adeno-associated virus for the generation of autologous, gene-modified tumor vaccines: evidence for a high transduction efficiency into primary epithelial cancer cells
To explore the potential of recombinant vectors based on recombinant adeno-associated virus (rAAV) for cancer vaccination, we investigated the transduction efficiency of rAAV into cancer cells ex vivo. Infection of human epithelial cancer cell lines with rAAV carrying reporter genes encoding beta-ga...
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Veröffentlicht in: | Human gene therapy 1998-05, Vol.9 (7), p.1049-1059 |
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creator | Maass, G Bogedain, C Scheer, U Michl, D Hörer, M Braun-Falco, M Volkenandt, M Schadendorf, D Wendtner, C M Winnacker, E L Kotin, R M Hallek, M |
description | To explore the potential of recombinant vectors based on recombinant adeno-associated virus (rAAV) for cancer vaccination, we investigated the transduction efficiency of rAAV into cancer cells ex vivo. Infection of human epithelial cancer cell lines with rAAV carrying reporter genes encoding beta-galactosidase (rAAV/LacZ) or luciferase (rAAV/Luc) resulted in high levels of reporter gene expression (>90% positive cells). In marked contrast, rAAV poorly transduced all murine tumor cell lines, as well as human hematopoietic cell lines. Either irradiation or adenovirus infection of tumor cells prior to rAAV infection induced a 10- to 100-fold increase of reporter gene expression. To determine the transduction efficiency of rAAV into primary cancer cells, freshly isolated, irradiated tumor cells from malignant melanoma and ovarian carcinoma patients were infected with rAAV/Luc, resulting in up to 6.9-fold higher levels of gene expression than in a HeLa tumor cell line. Time course experiments with freshly isolated tumor cells infected with rAAV/Luc showed maximal levels of luciferase expression between days 3 and 9 posttransduction. Simultaneous infection of primary tumor cells with up to three rAAV vectors containing genes encoding the immunostimulatory proteins B7-2 (CD86), p35 subunit of IL-12, and p40 subunit of IL-12 resulted in high expression of B7-2 in more than 90% of the tumor cells and in the secretion of high levels of IL-12. Taken together, our results demonstrate that rAAV efficiently transduces freshly isolated human, epithelial tumor cells and might therefore be a potent tool to produce improved, gene-modified cancer vaccines. |
doi_str_mv | 10.1089/hum.1998.9.7-1049 |
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Infection of human epithelial cancer cell lines with rAAV carrying reporter genes encoding beta-galactosidase (rAAV/LacZ) or luciferase (rAAV/Luc) resulted in high levels of reporter gene expression (>90% positive cells). In marked contrast, rAAV poorly transduced all murine tumor cell lines, as well as human hematopoietic cell lines. Either irradiation or adenovirus infection of tumor cells prior to rAAV infection induced a 10- to 100-fold increase of reporter gene expression. To determine the transduction efficiency of rAAV into primary cancer cells, freshly isolated, irradiated tumor cells from malignant melanoma and ovarian carcinoma patients were infected with rAAV/Luc, resulting in up to 6.9-fold higher levels of gene expression than in a HeLa tumor cell line. Time course experiments with freshly isolated tumor cells infected with rAAV/Luc showed maximal levels of luciferase expression between days 3 and 9 posttransduction. Simultaneous infection of primary tumor cells with up to three rAAV vectors containing genes encoding the immunostimulatory proteins B7-2 (CD86), p35 subunit of IL-12, and p40 subunit of IL-12 resulted in high expression of B7-2 in more than 90% of the tumor cells and in the secretion of high levels of IL-12. Taken together, our results demonstrate that rAAV efficiently transduces freshly isolated human, epithelial tumor cells and might therefore be a potent tool to produce improved, gene-modified cancer vaccines.</description><identifier>ISSN: 1043-0342</identifier><identifier>EISSN: 1557-7422</identifier><identifier>DOI: 10.1089/hum.1998.9.7-1049</identifier><identifier>PMID: 9607416</identifier><language>eng</language><publisher>United States</publisher><subject>Antigens, CD - genetics ; B7-2 Antigen ; Cancer Vaccines ; Dependovirus ; Epithelial Cells - metabolism ; Female ; Gene Transfer Techniques ; HeLa Cells ; HT29 Cells ; Humans ; Melanoma ; Membrane Glycoproteins - genetics ; Ovarian Neoplasms ; Recombination, Genetic ; Tumor Cells, Cultured ; X-Rays</subject><ispartof>Human gene therapy, 1998-05, Vol.9 (7), p.1049-1059</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c329t-952a2348c25cb76cb8e2b93a5823ad726e1dec427fcfd17a03b0a995da9ed3063</citedby><cites>FETCH-LOGICAL-c329t-952a2348c25cb76cb8e2b93a5823ad726e1dec427fcfd17a03b0a995da9ed3063</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,3042,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9607416$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Maass, G</creatorcontrib><creatorcontrib>Bogedain, C</creatorcontrib><creatorcontrib>Scheer, U</creatorcontrib><creatorcontrib>Michl, D</creatorcontrib><creatorcontrib>Hörer, M</creatorcontrib><creatorcontrib>Braun-Falco, M</creatorcontrib><creatorcontrib>Volkenandt, M</creatorcontrib><creatorcontrib>Schadendorf, D</creatorcontrib><creatorcontrib>Wendtner, C M</creatorcontrib><creatorcontrib>Winnacker, E L</creatorcontrib><creatorcontrib>Kotin, R M</creatorcontrib><creatorcontrib>Hallek, M</creatorcontrib><title>Recombinant adeno-associated virus for the generation of autologous, gene-modified tumor vaccines: evidence for a high transduction efficiency into primary epithelial cancer cells</title><title>Human gene therapy</title><addtitle>Hum Gene Ther</addtitle><description>To explore the potential of recombinant vectors based on recombinant adeno-associated virus (rAAV) for cancer vaccination, we investigated the transduction efficiency of rAAV into cancer cells ex vivo. Infection of human epithelial cancer cell lines with rAAV carrying reporter genes encoding beta-galactosidase (rAAV/LacZ) or luciferase (rAAV/Luc) resulted in high levels of reporter gene expression (>90% positive cells). In marked contrast, rAAV poorly transduced all murine tumor cell lines, as well as human hematopoietic cell lines. Either irradiation or adenovirus infection of tumor cells prior to rAAV infection induced a 10- to 100-fold increase of reporter gene expression. To determine the transduction efficiency of rAAV into primary cancer cells, freshly isolated, irradiated tumor cells from malignant melanoma and ovarian carcinoma patients were infected with rAAV/Luc, resulting in up to 6.9-fold higher levels of gene expression than in a HeLa tumor cell line. Time course experiments with freshly isolated tumor cells infected with rAAV/Luc showed maximal levels of luciferase expression between days 3 and 9 posttransduction. Simultaneous infection of primary tumor cells with up to three rAAV vectors containing genes encoding the immunostimulatory proteins B7-2 (CD86), p35 subunit of IL-12, and p40 subunit of IL-12 resulted in high expression of B7-2 in more than 90% of the tumor cells and in the secretion of high levels of IL-12. Taken together, our results demonstrate that rAAV efficiently transduces freshly isolated human, epithelial tumor cells and might therefore be a potent tool to produce improved, gene-modified cancer vaccines.</description><subject>Antigens, CD - genetics</subject><subject>B7-2 Antigen</subject><subject>Cancer Vaccines</subject><subject>Dependovirus</subject><subject>Epithelial Cells - metabolism</subject><subject>Female</subject><subject>Gene Transfer Techniques</subject><subject>HeLa Cells</subject><subject>HT29 Cells</subject><subject>Humans</subject><subject>Melanoma</subject><subject>Membrane Glycoproteins - genetics</subject><subject>Ovarian Neoplasms</subject><subject>Recombination, Genetic</subject><subject>Tumor Cells, Cultured</subject><subject>X-Rays</subject><issn>1043-0342</issn><issn>1557-7422</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkctq3DAUhk1pSdO0D9BFQauu6qkulmV1V0J6gUAhpGtxLB3PqNjSVJIH8lx5wWgmQ7ddSaD__3QOX9O8Z3TD6KA_79Zlw7QeNnqjWkY7_aK5ZFKqVnWcv6x32omWio6_bt7k_IdSJmSvLpoL3VPVsf6yebxDG5fRBwiFgMMQW8g5Wg8FHTn4tGYyxUTKDskWAyYoPgYSJwJriXPcxjV_Or20S3R-8rVV1qU2DmCtD5i_EDz4CrZ4AgHZ-e2OlAQhu9WeaDhN3voaeSA-lEj2yS-QHgjuff139jATCxWQiMV5zm-bVxPMGd-dz6vm97eb--sf7e2v7z-vv962VnBdWi05cNENlks7qt6OA_JRC5ADF-AU75E5tB1Xk50cU0DFSEFr6UCjE7QXV83HZ-4-xb8r5mIWn48TQMC6tlFaU6qk-m-Q9R1jUskaZM9Bm2LOCSdzXtUwao5GTTVqjkaNNsocjdbOhzN8HRd0_xpnheIJppqiTg</recordid><startdate>19980501</startdate><enddate>19980501</enddate><creator>Maass, G</creator><creator>Bogedain, C</creator><creator>Scheer, U</creator><creator>Michl, D</creator><creator>Hörer, M</creator><creator>Braun-Falco, M</creator><creator>Volkenandt, M</creator><creator>Schadendorf, D</creator><creator>Wendtner, C M</creator><creator>Winnacker, E L</creator><creator>Kotin, R M</creator><creator>Hallek, M</creator><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>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>19980501</creationdate><title>Recombinant adeno-associated virus for the generation of autologous, gene-modified tumor vaccines: evidence for a high transduction efficiency into primary epithelial cancer cells</title><author>Maass, G ; Bogedain, C ; Scheer, U ; Michl, D ; Hörer, M ; Braun-Falco, M ; Volkenandt, M ; Schadendorf, D ; Wendtner, C M ; Winnacker, E L ; Kotin, R M ; Hallek, M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c329t-952a2348c25cb76cb8e2b93a5823ad726e1dec427fcfd17a03b0a995da9ed3063</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Antigens, CD - genetics</topic><topic>B7-2 Antigen</topic><topic>Cancer Vaccines</topic><topic>Dependovirus</topic><topic>Epithelial Cells - metabolism</topic><topic>Female</topic><topic>Gene Transfer Techniques</topic><topic>HeLa Cells</topic><topic>HT29 Cells</topic><topic>Humans</topic><topic>Melanoma</topic><topic>Membrane Glycoproteins - genetics</topic><topic>Ovarian Neoplasms</topic><topic>Recombination, Genetic</topic><topic>Tumor Cells, Cultured</topic><topic>X-Rays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Maass, G</creatorcontrib><creatorcontrib>Bogedain, C</creatorcontrib><creatorcontrib>Scheer, U</creatorcontrib><creatorcontrib>Michl, D</creatorcontrib><creatorcontrib>Hörer, M</creatorcontrib><creatorcontrib>Braun-Falco, M</creatorcontrib><creatorcontrib>Volkenandt, M</creatorcontrib><creatorcontrib>Schadendorf, D</creatorcontrib><creatorcontrib>Wendtner, C M</creatorcontrib><creatorcontrib>Winnacker, E L</creatorcontrib><creatorcontrib>Kotin, R M</creatorcontrib><creatorcontrib>Hallek, M</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Human gene therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Maass, G</au><au>Bogedain, C</au><au>Scheer, U</au><au>Michl, D</au><au>Hörer, M</au><au>Braun-Falco, M</au><au>Volkenandt, M</au><au>Schadendorf, D</au><au>Wendtner, C M</au><au>Winnacker, E L</au><au>Kotin, R M</au><au>Hallek, M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Recombinant adeno-associated virus for the generation of autologous, gene-modified tumor vaccines: evidence for a high transduction efficiency into primary epithelial cancer cells</atitle><jtitle>Human gene therapy</jtitle><addtitle>Hum Gene Ther</addtitle><date>1998-05-01</date><risdate>1998</risdate><volume>9</volume><issue>7</issue><spage>1049</spage><epage>1059</epage><pages>1049-1059</pages><issn>1043-0342</issn><eissn>1557-7422</eissn><abstract>To explore the potential of recombinant vectors based on recombinant adeno-associated virus (rAAV) for cancer vaccination, we investigated the transduction efficiency of rAAV into cancer cells ex vivo. Infection of human epithelial cancer cell lines with rAAV carrying reporter genes encoding beta-galactosidase (rAAV/LacZ) or luciferase (rAAV/Luc) resulted in high levels of reporter gene expression (>90% positive cells). In marked contrast, rAAV poorly transduced all murine tumor cell lines, as well as human hematopoietic cell lines. Either irradiation or adenovirus infection of tumor cells prior to rAAV infection induced a 10- to 100-fold increase of reporter gene expression. To determine the transduction efficiency of rAAV into primary cancer cells, freshly isolated, irradiated tumor cells from malignant melanoma and ovarian carcinoma patients were infected with rAAV/Luc, resulting in up to 6.9-fold higher levels of gene expression than in a HeLa tumor cell line. Time course experiments with freshly isolated tumor cells infected with rAAV/Luc showed maximal levels of luciferase expression between days 3 and 9 posttransduction. Simultaneous infection of primary tumor cells with up to three rAAV vectors containing genes encoding the immunostimulatory proteins B7-2 (CD86), p35 subunit of IL-12, and p40 subunit of IL-12 resulted in high expression of B7-2 in more than 90% of the tumor cells and in the secretion of high levels of IL-12. Taken together, our results demonstrate that rAAV efficiently transduces freshly isolated human, epithelial tumor cells and might therefore be a potent tool to produce improved, gene-modified cancer vaccines.</abstract><cop>United States</cop><pmid>9607416</pmid><doi>10.1089/hum.1998.9.7-1049</doi><tpages>11</tpages></addata></record> |
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source | MEDLINE; 美国Mary Ann Liebert出版公司期刊(NSTL购买) |
subjects | Antigens, CD - genetics B7-2 Antigen Cancer Vaccines Dependovirus Epithelial Cells - metabolism Female Gene Transfer Techniques HeLa Cells HT29 Cells Humans Melanoma Membrane Glycoproteins - genetics Ovarian Neoplasms Recombination, Genetic Tumor Cells, Cultured X-Rays |
title | Recombinant adeno-associated virus for the generation of autologous, gene-modified tumor vaccines: evidence for a high transduction efficiency into primary epithelial cancer cells |
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