Oncolytic H-1 Parvovirus Shows Safety and Signs of Immunogenic Activity in a First Phase I/IIa Glioblastoma Trial
Oncolytic virotherapy may be a means of improving the dismal prognosis of malignant brain tumors. The rat H-1 parvovirus (H-1PV) suppresses tumors in preclinical glioma models, through both direct oncolysis and stimulation of anticancer immune responses. This was the basis of ParvOryx01, the first p...
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| Veröffentlicht in: | Molecular therapy 2017-12, Vol.25 (12), p.2620-2634 |
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| creator | Geletneky, Karsten Hajda, Jacek Angelova, Assia L. Leuchs, Barbara Capper, David Bartsch, Andreas J. Neumann, Jan-Oliver Schöning, Tilman Hüsing, Johannes Beelte, Birgit Kiprianova, Irina Roscher, Mandy Bhat, Rauf von Deimling, Andreas Brück, Wolfgang Just, Alexandra Frehtman, Veronika Löbhard, Stephanie Terletskaia-Ladwig, Elena Fry, Jeremy Jochims, Karin Daniel, Volker Krebs, Ottheinz Dahm, Michael Huber, Bernard Unterberg, Andreas Rommelaere, Jean |
| description | Oncolytic virotherapy may be a means of improving the dismal prognosis of malignant brain tumors. The rat H-1 parvovirus (H-1PV) suppresses tumors in preclinical glioma models, through both direct oncolysis and stimulation of anticancer immune responses. This was the basis of ParvOryx01, the first phase I/IIa clinical trial of an oncolytic parvovirus in recurrent glioblastoma patients. H-1PV (escalating dose) was administered via intratumoral or intravenous injection. Tumors were resected 9 days after treatment, and virus was re-administered around the resection cavity. Primary endpoints were safety and tolerability, virus distribution, and maximum tolerated dose (MTD). Progression-free and overall survival and levels of viral and immunological markers in the tumor and peripheral blood were also investigated. H-1PV treatment was safe and well tolerated, and no MTD was reached. The virus could cross the blood-brain/tumor barrier and spread widely through the tumor. It showed favorable pharmacokinetics, induced antibody formation in a dose-dependent manner, and triggered specific T cell responses. Markers of virus replication, microglia/macrophage activation, and cytotoxic T cell infiltration were detected in infected tumors, suggesting that H-1PV may trigger an immunogenic stimulus. Median survival was extended in comparison with recent meta-analyses. Altogether, ParvOryx01 results provide an impetus for further H-1PV clinical development.
Through an early-phase clinical trial in recurrent glioblastoma patients, Geletneky et al. show that the oncolytic H-1 parvovirus is safe, well tolerated, and able to establish an immunogenic tumor microenvironment. Blood-brain/tumor crossing and favorable survival compared with historical controls make this virus an interesting candidate for further clinical development. |
| doi_str_mv | 10.1016/j.ymthe.2017.08.016 |
| format | Article |
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Through an early-phase clinical trial in recurrent glioblastoma patients, Geletneky et al. show that the oncolytic H-1 parvovirus is safe, well tolerated, and able to establish an immunogenic tumor microenvironment. Blood-brain/tumor crossing and favorable survival compared with historical controls make this virus an interesting candidate for further clinical development.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1016/j.ymthe.2017.08.016</identifier><identifier>PMID: 28967558</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Aged ; Animal models ; Antineoplastic Combined Chemotherapy Protocols - adverse effects ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Brain cancer ; Brain tumors ; Cell activation ; clinical trial ; Consciousness ; Cytotoxicity ; Deoxyribonucleic acid ; DNA ; DNA methylation ; Female ; Gene Expression ; Genetic Therapy - adverse effects ; Genetic Therapy - methods ; Genetic Vectors - administration & dosage ; Genetic Vectors - genetics ; Genetic Vectors - immunology ; Glioblastoma ; Glioblastoma - genetics ; Glioblastoma - mortality ; Glioblastoma - pathology ; Glioblastoma - therapy ; Glioma ; H-1 parvovirus - genetics ; Humans ; Immunogenicity ; Immunotherapy ; Intravenous administration ; Laboratories ; Lymphocytes T ; Lymphocytes, Tumor-Infiltrating - immunology ; Lymphocytes, Tumor-Infiltrating - metabolism ; Lymphocytes, Tumor-Infiltrating - pathology ; Macrophages ; Male ; Metabolism ; Metastases ; Microglia ; Middle Aged ; Molecular Targeted Therapy ; Oncolysis ; oncolytic parvovirus ; Oncolytic Virotherapy - adverse effects ; Oncolytic Virotherapy - methods ; Oncolytic Viruses - genetics ; Original ; Parvoviruses ; Patients ; Peripheral blood ; Pharmacokinetics ; Proteins ; Radiation therapy ; Radiotherapy ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism ; T-Lymphocytes - pathology ; Transgenes ; Treatment Outcome ; tumor microenvironment ; Viruses</subject><ispartof>Molecular therapy, 2017-12, Vol.25 (12), p.2620-2634</ispartof><rights>2017 The Author(s)</rights><rights>Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.</rights><rights>2017. The Author(s)</rights><rights>2017 The Author(s) 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c553t-a80f6ccf280b815b7f5bdd726a370a4846d06ac5720f36b44a10c719b006ce1a3</citedby><cites>FETCH-LOGICAL-c553t-a80f6ccf280b815b7f5bdd726a370a4846d06ac5720f36b44a10c719b006ce1a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768665/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5768665/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28967558$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Geletneky, Karsten</creatorcontrib><creatorcontrib>Hajda, Jacek</creatorcontrib><creatorcontrib>Angelova, Assia L.</creatorcontrib><creatorcontrib>Leuchs, Barbara</creatorcontrib><creatorcontrib>Capper, David</creatorcontrib><creatorcontrib>Bartsch, Andreas J.</creatorcontrib><creatorcontrib>Neumann, Jan-Oliver</creatorcontrib><creatorcontrib>Schöning, Tilman</creatorcontrib><creatorcontrib>Hüsing, Johannes</creatorcontrib><creatorcontrib>Beelte, Birgit</creatorcontrib><creatorcontrib>Kiprianova, Irina</creatorcontrib><creatorcontrib>Roscher, Mandy</creatorcontrib><creatorcontrib>Bhat, Rauf</creatorcontrib><creatorcontrib>von Deimling, Andreas</creatorcontrib><creatorcontrib>Brück, Wolfgang</creatorcontrib><creatorcontrib>Just, Alexandra</creatorcontrib><creatorcontrib>Frehtman, Veronika</creatorcontrib><creatorcontrib>Löbhard, Stephanie</creatorcontrib><creatorcontrib>Terletskaia-Ladwig, Elena</creatorcontrib><creatorcontrib>Fry, Jeremy</creatorcontrib><creatorcontrib>Jochims, Karin</creatorcontrib><creatorcontrib>Daniel, Volker</creatorcontrib><creatorcontrib>Krebs, Ottheinz</creatorcontrib><creatorcontrib>Dahm, Michael</creatorcontrib><creatorcontrib>Huber, Bernard</creatorcontrib><creatorcontrib>Unterberg, Andreas</creatorcontrib><creatorcontrib>Rommelaere, Jean</creatorcontrib><title>Oncolytic H-1 Parvovirus Shows Safety and Signs of Immunogenic Activity in a First Phase I/IIa Glioblastoma Trial</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>Oncolytic virotherapy may be a means of improving the dismal prognosis of malignant brain tumors. The rat H-1 parvovirus (H-1PV) suppresses tumors in preclinical glioma models, through both direct oncolysis and stimulation of anticancer immune responses. This was the basis of ParvOryx01, the first phase I/IIa clinical trial of an oncolytic parvovirus in recurrent glioblastoma patients. H-1PV (escalating dose) was administered via intratumoral or intravenous injection. Tumors were resected 9 days after treatment, and virus was re-administered around the resection cavity. Primary endpoints were safety and tolerability, virus distribution, and maximum tolerated dose (MTD). Progression-free and overall survival and levels of viral and immunological markers in the tumor and peripheral blood were also investigated. H-1PV treatment was safe and well tolerated, and no MTD was reached. The virus could cross the blood-brain/tumor barrier and spread widely through the tumor. It showed favorable pharmacokinetics, induced antibody formation in a dose-dependent manner, and triggered specific T cell responses. Markers of virus replication, microglia/macrophage activation, and cytotoxic T cell infiltration were detected in infected tumors, suggesting that H-1PV may trigger an immunogenic stimulus. Median survival was extended in comparison with recent meta-analyses. Altogether, ParvOryx01 results provide an impetus for further H-1PV clinical development.
Through an early-phase clinical trial in recurrent glioblastoma patients, Geletneky et al. show that the oncolytic H-1 parvovirus is safe, well tolerated, and able to establish an immunogenic tumor microenvironment. Blood-brain/tumor crossing and favorable survival compared with historical controls make this virus an interesting candidate for further clinical development.</description><subject>Aged</subject><subject>Animal models</subject><subject>Antineoplastic Combined Chemotherapy Protocols - adverse effects</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Brain cancer</subject><subject>Brain tumors</subject><subject>Cell activation</subject><subject>clinical trial</subject><subject>Consciousness</subject><subject>Cytotoxicity</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Genetic Therapy - adverse effects</subject><subject>Genetic Therapy - methods</subject><subject>Genetic Vectors - administration & dosage</subject><subject>Genetic Vectors - genetics</subject><subject>Genetic Vectors - immunology</subject><subject>Glioblastoma</subject><subject>Glioblastoma - genetics</subject><subject>Glioblastoma - mortality</subject><subject>Glioblastoma - pathology</subject><subject>Glioblastoma - therapy</subject><subject>Glioma</subject><subject>H-1 parvovirus - genetics</subject><subject>Humans</subject><subject>Immunogenicity</subject><subject>Immunotherapy</subject><subject>Intravenous administration</subject><subject>Laboratories</subject><subject>Lymphocytes T</subject><subject>Lymphocytes, Tumor-Infiltrating - immunology</subject><subject>Lymphocytes, Tumor-Infiltrating - metabolism</subject><subject>Lymphocytes, Tumor-Infiltrating - pathology</subject><subject>Macrophages</subject><subject>Male</subject><subject>Metabolism</subject><subject>Metastases</subject><subject>Microglia</subject><subject>Middle Aged</subject><subject>Molecular Targeted Therapy</subject><subject>Oncolysis</subject><subject>oncolytic parvovirus</subject><subject>Oncolytic Virotherapy - adverse effects</subject><subject>Oncolytic Virotherapy - methods</subject><subject>Oncolytic Viruses - 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adverse effects</topic><topic>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</topic><topic>Brain cancer</topic><topic>Brain tumors</topic><topic>Cell activation</topic><topic>clinical trial</topic><topic>Consciousness</topic><topic>Cytotoxicity</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA methylation</topic><topic>Female</topic><topic>Gene Expression</topic><topic>Genetic Therapy - adverse effects</topic><topic>Genetic Therapy - methods</topic><topic>Genetic Vectors - administration & dosage</topic><topic>Genetic Vectors - genetics</topic><topic>Genetic Vectors - immunology</topic><topic>Glioblastoma</topic><topic>Glioblastoma - genetics</topic><topic>Glioblastoma - mortality</topic><topic>Glioblastoma - pathology</topic><topic>Glioblastoma - therapy</topic><topic>Glioma</topic><topic>H-1 parvovirus - genetics</topic><topic>Humans</topic><topic>Immunogenicity</topic><topic>Immunotherapy</topic><topic>Intravenous administration</topic><topic>Laboratories</topic><topic>Lymphocytes T</topic><topic>Lymphocytes, Tumor-Infiltrating - immunology</topic><topic>Lymphocytes, Tumor-Infiltrating - metabolism</topic><topic>Lymphocytes, Tumor-Infiltrating - pathology</topic><topic>Macrophages</topic><topic>Male</topic><topic>Metabolism</topic><topic>Metastases</topic><topic>Microglia</topic><topic>Middle Aged</topic><topic>Molecular Targeted Therapy</topic><topic>Oncolysis</topic><topic>oncolytic parvovirus</topic><topic>Oncolytic Virotherapy - adverse effects</topic><topic>Oncolytic Virotherapy - methods</topic><topic>Oncolytic Viruses - genetics</topic><topic>Original</topic><topic>Parvoviruses</topic><topic>Patients</topic><topic>Peripheral blood</topic><topic>Pharmacokinetics</topic><topic>Proteins</topic><topic>Radiation therapy</topic><topic>Radiotherapy</topic><topic>T-Lymphocytes - immunology</topic><topic>T-Lymphocytes - metabolism</topic><topic>T-Lymphocytes - pathology</topic><topic>Transgenes</topic><topic>Treatment Outcome</topic><topic>tumor microenvironment</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Geletneky, Karsten</creatorcontrib><creatorcontrib>Hajda, Jacek</creatorcontrib><creatorcontrib>Angelova, Assia L.</creatorcontrib><creatorcontrib>Leuchs, Barbara</creatorcontrib><creatorcontrib>Capper, David</creatorcontrib><creatorcontrib>Bartsch, Andreas J.</creatorcontrib><creatorcontrib>Neumann, Jan-Oliver</creatorcontrib><creatorcontrib>Schöning, Tilman</creatorcontrib><creatorcontrib>Hüsing, Johannes</creatorcontrib><creatorcontrib>Beelte, Birgit</creatorcontrib><creatorcontrib>Kiprianova, Irina</creatorcontrib><creatorcontrib>Roscher, Mandy</creatorcontrib><creatorcontrib>Bhat, Rauf</creatorcontrib><creatorcontrib>von Deimling, Andreas</creatorcontrib><creatorcontrib>Brück, Wolfgang</creatorcontrib><creatorcontrib>Just, Alexandra</creatorcontrib><creatorcontrib>Frehtman, Veronika</creatorcontrib><creatorcontrib>Löbhard, Stephanie</creatorcontrib><creatorcontrib>Terletskaia-Ladwig, Elena</creatorcontrib><creatorcontrib>Fry, Jeremy</creatorcontrib><creatorcontrib>Jochims, Karin</creatorcontrib><creatorcontrib>Daniel, Volker</creatorcontrib><creatorcontrib>Krebs, Ottheinz</creatorcontrib><creatorcontrib>Dahm, Michael</creatorcontrib><creatorcontrib>Huber, Bernard</creatorcontrib><creatorcontrib>Unterberg, Andreas</creatorcontrib><creatorcontrib>Rommelaere, Jean</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Biological Science Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Geletneky, Karsten</au><au>Hajda, Jacek</au><au>Angelova, Assia L.</au><au>Leuchs, Barbara</au><au>Capper, David</au><au>Bartsch, Andreas J.</au><au>Neumann, Jan-Oliver</au><au>Schöning, Tilman</au><au>Hüsing, Johannes</au><au>Beelte, Birgit</au><au>Kiprianova, Irina</au><au>Roscher, Mandy</au><au>Bhat, Rauf</au><au>von Deimling, Andreas</au><au>Brück, Wolfgang</au><au>Just, Alexandra</au><au>Frehtman, Veronika</au><au>Löbhard, Stephanie</au><au>Terletskaia-Ladwig, Elena</au><au>Fry, Jeremy</au><au>Jochims, Karin</au><au>Daniel, Volker</au><au>Krebs, Ottheinz</au><au>Dahm, Michael</au><au>Huber, Bernard</au><au>Unterberg, Andreas</au><au>Rommelaere, Jean</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Oncolytic H-1 Parvovirus Shows Safety and Signs of Immunogenic Activity in a First Phase I/IIa Glioblastoma Trial</atitle><jtitle>Molecular therapy</jtitle><addtitle>Mol Ther</addtitle><date>2017-12-06</date><risdate>2017</risdate><volume>25</volume><issue>12</issue><spage>2620</spage><epage>2634</epage><pages>2620-2634</pages><issn>1525-0016</issn><eissn>1525-0024</eissn><abstract>Oncolytic virotherapy may be a means of improving the dismal prognosis of malignant brain tumors. The rat H-1 parvovirus (H-1PV) suppresses tumors in preclinical glioma models, through both direct oncolysis and stimulation of anticancer immune responses. This was the basis of ParvOryx01, the first phase I/IIa clinical trial of an oncolytic parvovirus in recurrent glioblastoma patients. H-1PV (escalating dose) was administered via intratumoral or intravenous injection. Tumors were resected 9 days after treatment, and virus was re-administered around the resection cavity. Primary endpoints were safety and tolerability, virus distribution, and maximum tolerated dose (MTD). Progression-free and overall survival and levels of viral and immunological markers in the tumor and peripheral blood were also investigated. H-1PV treatment was safe and well tolerated, and no MTD was reached. The virus could cross the blood-brain/tumor barrier and spread widely through the tumor. It showed favorable pharmacokinetics, induced antibody formation in a dose-dependent manner, and triggered specific T cell responses. Markers of virus replication, microglia/macrophage activation, and cytotoxic T cell infiltration were detected in infected tumors, suggesting that H-1PV may trigger an immunogenic stimulus. Median survival was extended in comparison with recent meta-analyses. Altogether, ParvOryx01 results provide an impetus for further H-1PV clinical development.
Through an early-phase clinical trial in recurrent glioblastoma patients, Geletneky et al. show that the oncolytic H-1 parvovirus is safe, well tolerated, and able to establish an immunogenic tumor microenvironment. Blood-brain/tumor crossing and favorable survival compared with historical controls make this virus an interesting candidate for further clinical development.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>28967558</pmid><doi>10.1016/j.ymthe.2017.08.016</doi><tpages>15</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1525-0016 |
| ispartof | Molecular therapy, 2017-12, Vol.25 (12), p.2620-2634 |
| issn | 1525-0016 1525-0024 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5768665 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Aged Animal models Antineoplastic Combined Chemotherapy Protocols - adverse effects Antineoplastic Combined Chemotherapy Protocols - therapeutic use Brain cancer Brain tumors Cell activation clinical trial Consciousness Cytotoxicity Deoxyribonucleic acid DNA DNA methylation Female Gene Expression Genetic Therapy - adverse effects Genetic Therapy - methods Genetic Vectors - administration & dosage Genetic Vectors - genetics Genetic Vectors - immunology Glioblastoma Glioblastoma - genetics Glioblastoma - mortality Glioblastoma - pathology Glioblastoma - therapy Glioma H-1 parvovirus - genetics Humans Immunogenicity Immunotherapy Intravenous administration Laboratories Lymphocytes T Lymphocytes, Tumor-Infiltrating - immunology Lymphocytes, Tumor-Infiltrating - metabolism Lymphocytes, Tumor-Infiltrating - pathology Macrophages Male Metabolism Metastases Microglia Middle Aged Molecular Targeted Therapy Oncolysis oncolytic parvovirus Oncolytic Virotherapy - adverse effects Oncolytic Virotherapy - methods Oncolytic Viruses - genetics Original Parvoviruses Patients Peripheral blood Pharmacokinetics Proteins Radiation therapy Radiotherapy T-Lymphocytes - immunology T-Lymphocytes - metabolism T-Lymphocytes - pathology Transgenes Treatment Outcome tumor microenvironment Viruses |
| title | Oncolytic H-1 Parvovirus Shows Safety and Signs of Immunogenic Activity in a First Phase I/IIa Glioblastoma Trial |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-01T23%3A52%3A17IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Oncolytic%20H-1%20Parvovirus%20Shows%20Safety%20and%20Signs%20of%20Immunogenic%20Activity%20in%20a%20First%20Phase%20I/IIa%20Glioblastoma%20Trial&rft.jtitle=Molecular%20therapy&rft.au=Geletneky,%20Karsten&rft.date=2017-12-06&rft.volume=25&rft.issue=12&rft.spage=2620&rft.epage=2634&rft.pages=2620-2634&rft.issn=1525-0016&rft.eissn=1525-0024&rft_id=info:doi/10.1016/j.ymthe.2017.08.016&rft_dat=%3Cproquest_pubme%3E2198010705%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2198010705&rft_id=info:pmid/28967558&rft_els_id=S1525001617303787&rfr_iscdi=true |