A recombinant modified vaccinia ankara vaccine encoding Epstein-Barr Virus (EBV) target antigens: a phase I trial in UK patients with EBV-positive cancer
Epstein-Barr virus (EBV) is associated with several cancers in which the tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumor antigens. A phase I trial was conducted to demonstrate the sa...
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| Veröffentlicht in: | Clinical cancer research 2014-10, Vol.20 (19), p.5009-5022 |
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| creator | Taylor, Graham S Jia, Hui Harrington, Kevin Lee, Lip Wai Turner, James Ladell, Kristin Price, David A Tanday, Manjit Matthews, Jen Roberts, Claudia Edwards, Ceri McGuigan, Lesley Hartley, Andrew Wilson, Steve Hui, Edwin P Chan, Anthony T C Rickinson, Alan B Steven, Neil M |
| description | Epstein-Barr virus (EBV) is associated with several cancers in which the tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumor antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses.
Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC) received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5 × 10(7) and 5 × 10(8) plaque-forming units (pfu). Blood samples were taken at screening, after each vaccine cycle, and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations.
Vaccination was generally well tolerated. Immunity increased after vaccination to at least one antigen in 8 of 14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments, respectively.
MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South-East Asia where NPC is most common. The highest dose (5 × 10(8) pfu) is recommended for investigation in current phase IB and II trials. |
| doi_str_mv | 10.1158/1078-0432.CCR-14-1122-T |
| format | Article |
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Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC) received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5 × 10(7) and 5 × 10(8) plaque-forming units (pfu). Blood samples were taken at screening, after each vaccine cycle, and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations.
Vaccination was generally well tolerated. Immunity increased after vaccination to at least one antigen in 8 of 14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments, respectively.
MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South-East Asia where NPC is most common. The highest dose (5 × 10(8) pfu) is recommended for investigation in current phase IB and II trials.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-14-1122-T</identifier><identifier>PMID: 25124688</identifier><language>eng</language><publisher>United States</publisher><subject>Adult ; Aged ; Cancer Vaccines - administration & dosage ; Cancer Vaccines - immunology ; Combined Modality Therapy ; Epitopes, T-Lymphocyte - immunology ; Epstein-Barr Virus Infections - complications ; Epstein-Barr Virus Infections - virology ; Epstein-Barr Virus Nuclear Antigens - genetics ; Epstein-Barr Virus Nuclear Antigens - immunology ; Female ; Herpesvirus 4, Human - genetics ; Herpesvirus 4, Human - immunology ; Humans ; Immunophenotyping ; Lymphocyte Count ; Male ; Middle Aged ; Neoplasm Staging ; Neoplasms - diagnosis ; Neoplasms - etiology ; Neoplasms - prevention & control ; Neoplasms - therapy ; T-Cell Antigen Receptor Specificity ; T-Lymphocyte Subsets - immunology ; T-Lymphocyte Subsets - metabolism ; Treatment Outcome ; Vaccination ; Vaccinia virus - genetics ; Vaccinia virus - immunology ; Viral Load</subject><ispartof>Clinical cancer research, 2014-10, Vol.20 (19), p.5009-5022</ispartof><rights>2014 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c471t-4aa4f956b2bdc487ef5172009d4f23a1f702b93425ffe12705c705b49c248e8d3</citedby><cites>FETCH-LOGICAL-c471t-4aa4f956b2bdc487ef5172009d4f23a1f702b93425ffe12705c705b49c248e8d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3343,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25124688$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Taylor, Graham S</creatorcontrib><creatorcontrib>Jia, Hui</creatorcontrib><creatorcontrib>Harrington, Kevin</creatorcontrib><creatorcontrib>Lee, Lip Wai</creatorcontrib><creatorcontrib>Turner, James</creatorcontrib><creatorcontrib>Ladell, Kristin</creatorcontrib><creatorcontrib>Price, David A</creatorcontrib><creatorcontrib>Tanday, Manjit</creatorcontrib><creatorcontrib>Matthews, Jen</creatorcontrib><creatorcontrib>Roberts, Claudia</creatorcontrib><creatorcontrib>Edwards, Ceri</creatorcontrib><creatorcontrib>McGuigan, Lesley</creatorcontrib><creatorcontrib>Hartley, Andrew</creatorcontrib><creatorcontrib>Wilson, Steve</creatorcontrib><creatorcontrib>Hui, Edwin P</creatorcontrib><creatorcontrib>Chan, Anthony T C</creatorcontrib><creatorcontrib>Rickinson, Alan B</creatorcontrib><creatorcontrib>Steven, Neil M</creatorcontrib><title>A recombinant modified vaccinia ankara vaccine encoding Epstein-Barr Virus (EBV) target antigens: a phase I trial in UK patients with EBV-positive cancer</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Epstein-Barr virus (EBV) is associated with several cancers in which the tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumor antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses.
Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC) received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5 × 10(7) and 5 × 10(8) plaque-forming units (pfu). Blood samples were taken at screening, after each vaccine cycle, and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations.
Vaccination was generally well tolerated. Immunity increased after vaccination to at least one antigen in 8 of 14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments, respectively.
MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South-East Asia where NPC is most common. The highest dose (5 × 10(8) pfu) is recommended for investigation in current phase IB and II trials.</description><subject>Adult</subject><subject>Aged</subject><subject>Cancer Vaccines - administration & dosage</subject><subject>Cancer Vaccines - immunology</subject><subject>Combined Modality Therapy</subject><subject>Epitopes, T-Lymphocyte - immunology</subject><subject>Epstein-Barr Virus Infections - complications</subject><subject>Epstein-Barr Virus Infections - virology</subject><subject>Epstein-Barr Virus Nuclear Antigens - genetics</subject><subject>Epstein-Barr Virus Nuclear Antigens - immunology</subject><subject>Female</subject><subject>Herpesvirus 4, Human - genetics</subject><subject>Herpesvirus 4, Human - immunology</subject><subject>Humans</subject><subject>Immunophenotyping</subject><subject>Lymphocyte Count</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Neoplasm Staging</subject><subject>Neoplasms - diagnosis</subject><subject>Neoplasms - etiology</subject><subject>Neoplasms - prevention & control</subject><subject>Neoplasms - therapy</subject><subject>T-Cell Antigen Receptor Specificity</subject><subject>T-Lymphocyte Subsets - immunology</subject><subject>T-Lymphocyte Subsets - metabolism</subject><subject>Treatment Outcome</subject><subject>Vaccination</subject><subject>Vaccinia virus - genetics</subject><subject>Vaccinia virus - immunology</subject><subject>Viral Load</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkd1uEzEQhVcIREvhFWAuy4WL7bX3hwukNgpQUQkJpb21Zr2ziWHjXWwniEfhbXHUtIILyx75nDNH-orijeAXQujmneB1w7gq5cVi8Y0JxYSQkq2eFKdC65qVstJP8_tBdVK8iPE750IJrp4XJ1ILqaqmOS3-XEIgO20759En2E69Gxz1sEdrnXcI6H9gwONMQN5miV_Dco6JnGdXGALcubCLcL68unsLCcOaUvYltyYf3wPCvMFIcA0pOBzBebj9AjMmRz5F-OXSBrKTzVN0ye0JLHpL4WXxbMAx0qvjfVbcflyuFp_ZzddP14vLG2ZVLRJTiGpoddXJrreqqWnQopact70aZIliqLns2lJJPQwkZM21zadTrZWqoaYvz4oP97nzrttSb3OpgKOZg9ti-G0mdOb_H-82Zj3tjSoV17zKAefHgDD93FFMZuuipXFET9Mumsyr4m2lhM7S-l5qwxRjoOFxjeDmANYckJkDMpPBGqHMAaxZZefrf1s--h5Iln8BCwOhHg</recordid><startdate>20141001</startdate><enddate>20141001</enddate><creator>Taylor, Graham S</creator><creator>Jia, Hui</creator><creator>Harrington, Kevin</creator><creator>Lee, Lip Wai</creator><creator>Turner, James</creator><creator>Ladell, Kristin</creator><creator>Price, David A</creator><creator>Tanday, Manjit</creator><creator>Matthews, Jen</creator><creator>Roberts, Claudia</creator><creator>Edwards, Ceri</creator><creator>McGuigan, Lesley</creator><creator>Hartley, Andrew</creator><creator>Wilson, Steve</creator><creator>Hui, Edwin P</creator><creator>Chan, Anthony T C</creator><creator>Rickinson, Alan B</creator><creator>Steven, Neil 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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20141001</creationdate><title>A recombinant modified vaccinia ankara vaccine encoding Epstein-Barr Virus (EBV) target antigens: a phase I trial in UK patients with EBV-positive cancer</title><author>Taylor, Graham S ; Jia, Hui ; Harrington, Kevin ; Lee, Lip Wai ; Turner, James ; Ladell, Kristin ; Price, David A ; Tanday, Manjit ; Matthews, Jen ; Roberts, Claudia ; Edwards, Ceri ; McGuigan, Lesley ; Hartley, Andrew ; Wilson, Steve ; Hui, Edwin P ; Chan, Anthony T C ; Rickinson, Alan B ; Steven, Neil M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c471t-4aa4f956b2bdc487ef5172009d4f23a1f702b93425ffe12705c705b49c248e8d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Cancer Vaccines - administration & dosage</topic><topic>Cancer Vaccines - immunology</topic><topic>Combined Modality Therapy</topic><topic>Epitopes, T-Lymphocyte - immunology</topic><topic>Epstein-Barr Virus Infections - complications</topic><topic>Epstein-Barr Virus Infections - virology</topic><topic>Epstein-Barr Virus Nuclear Antigens - genetics</topic><topic>Epstein-Barr Virus Nuclear Antigens - immunology</topic><topic>Female</topic><topic>Herpesvirus 4, Human - genetics</topic><topic>Herpesvirus 4, Human - immunology</topic><topic>Humans</topic><topic>Immunophenotyping</topic><topic>Lymphocyte Count</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Neoplasm Staging</topic><topic>Neoplasms - diagnosis</topic><topic>Neoplasms - etiology</topic><topic>Neoplasms - prevention & control</topic><topic>Neoplasms - therapy</topic><topic>T-Cell Antigen Receptor Specificity</topic><topic>T-Lymphocyte Subsets - immunology</topic><topic>T-Lymphocyte Subsets - metabolism</topic><topic>Treatment Outcome</topic><topic>Vaccination</topic><topic>Vaccinia virus - genetics</topic><topic>Vaccinia virus - immunology</topic><topic>Viral Load</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Taylor, Graham S</creatorcontrib><creatorcontrib>Jia, Hui</creatorcontrib><creatorcontrib>Harrington, Kevin</creatorcontrib><creatorcontrib>Lee, Lip Wai</creatorcontrib><creatorcontrib>Turner, James</creatorcontrib><creatorcontrib>Ladell, Kristin</creatorcontrib><creatorcontrib>Price, David A</creatorcontrib><creatorcontrib>Tanday, Manjit</creatorcontrib><creatorcontrib>Matthews, Jen</creatorcontrib><creatorcontrib>Roberts, Claudia</creatorcontrib><creatorcontrib>Edwards, Ceri</creatorcontrib><creatorcontrib>McGuigan, Lesley</creatorcontrib><creatorcontrib>Hartley, Andrew</creatorcontrib><creatorcontrib>Wilson, Steve</creatorcontrib><creatorcontrib>Hui, Edwin P</creatorcontrib><creatorcontrib>Chan, Anthony T C</creatorcontrib><creatorcontrib>Rickinson, Alan B</creatorcontrib><creatorcontrib>Steven, Neil 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>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Taylor, Graham S</au><au>Jia, Hui</au><au>Harrington, Kevin</au><au>Lee, Lip Wai</au><au>Turner, James</au><au>Ladell, Kristin</au><au>Price, David A</au><au>Tanday, Manjit</au><au>Matthews, Jen</au><au>Roberts, Claudia</au><au>Edwards, Ceri</au><au>McGuigan, Lesley</au><au>Hartley, Andrew</au><au>Wilson, Steve</au><au>Hui, Edwin P</au><au>Chan, Anthony T C</au><au>Rickinson, Alan B</au><au>Steven, Neil M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A recombinant modified vaccinia ankara vaccine encoding Epstein-Barr Virus (EBV) target antigens: a phase I trial in UK patients with EBV-positive cancer</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2014-10-01</date><risdate>2014</risdate><volume>20</volume><issue>19</issue><spage>5009</spage><epage>5022</epage><pages>5009-5022</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Epstein-Barr virus (EBV) is associated with several cancers in which the tumor cells express EBV antigens EBNA1 and LMP2. A therapeutic vaccine comprising a recombinant vaccinia virus, MVA-EL, was designed to boost immunity to these tumor antigens. A phase I trial was conducted to demonstrate the safety and immunogenicity of MVA-EL across a range of doses.
Sixteen patients in the United Kingdom (UK) with EBV-positive nasopharyngeal carcinoma (NPC) received three intradermal vaccinations of MVA-EL at 3-weekly intervals at dose levels between 5 × 10(7) and 5 × 10(8) plaque-forming units (pfu). Blood samples were taken at screening, after each vaccine cycle, and during the post-vaccination period. T-cell responses were measured using IFNγ ELISpot assays with overlapping EBNA1/LMP2 peptide mixes or HLA-matched epitope peptides. Polychromatic flow cytometry was used to characterize functionally responsive T-cell populations.
Vaccination was generally well tolerated. Immunity increased after vaccination to at least one antigen in 8 of 14 patients (7/14, EBNA1; 6/14, LMP2), including recognition of epitopes that vary between EBV strains associated with different ethnic groups. Immunophenotypic analysis revealed that vaccination induced differentiation and functional diversification of responsive T-cell populations specific for EBNA1 and LMP2 within the CD4 and CD8 compartments, respectively.
MVA-EL is safe and immunogenic across diverse ethnicities and thus suitable for use in trials against different EBV-positive cancers globally as well as in South-East Asia where NPC is most common. The highest dose (5 × 10(8) pfu) is recommended for investigation in current phase IB and II trials.</abstract><cop>United States</cop><pmid>25124688</pmid><doi>10.1158/1078-0432.CCR-14-1122-T</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Clinical cancer research, 2014-10, Vol.20 (19), p.5009-5022 |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adult Aged Cancer Vaccines - administration & dosage Cancer Vaccines - immunology Combined Modality Therapy Epitopes, T-Lymphocyte - immunology Epstein-Barr Virus Infections - complications Epstein-Barr Virus Infections - virology Epstein-Barr Virus Nuclear Antigens - genetics Epstein-Barr Virus Nuclear Antigens - immunology Female Herpesvirus 4, Human - genetics Herpesvirus 4, Human - immunology Humans Immunophenotyping Lymphocyte Count Male Middle Aged Neoplasm Staging Neoplasms - diagnosis Neoplasms - etiology Neoplasms - prevention & control Neoplasms - therapy T-Cell Antigen Receptor Specificity T-Lymphocyte Subsets - immunology T-Lymphocyte Subsets - metabolism Treatment Outcome Vaccination Vaccinia virus - genetics Vaccinia virus - immunology Viral Load |
| title | A recombinant modified vaccinia ankara vaccine encoding Epstein-Barr Virus (EBV) target antigens: a phase I trial in UK patients with EBV-positive cancer |
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