A Novel DNA Vaccine Platform Enhances Neo-antigen-like T Cell Responses against WT1 to Break Tolerance and Induce Anti-tumor Immunity
Tumor-associated antigens have emerged as important immunotherapeutic targets in the fight against cancer. Germline tumor antigens, such as WT1, Wilms’ tumor gene 1, are overexpressed in many human malignancies but have low expression in somatic tissues. Recent vaccination approaches to target WT1 h...
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| Veröffentlicht in: | Molecular therapy 2017-04, Vol.25 (4), p.976-988 |
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| creator | Walters, Jewell N. Ferraro, Bernadette Duperret, Elizabeth K. Kraynyak, Kimberly A. Chu, Jaemi Saint-Fleur, Ashley Yan, Jian Levitsky, Hy Khan, Amir S. Sardesai, Niranjan Y. Weiner, David B. |
| description | Tumor-associated antigens have emerged as important immunotherapeutic targets in the fight against cancer. Germline tumor antigens, such as WT1, Wilms’ tumor gene 1, are overexpressed in many human malignancies but have low expression in somatic tissues. Recent vaccination approaches to target WT1 have been hampered by poor in vivo immune potency, likely due to the conserved self-antigen nature of WT1. In this study, we use a novel synthetic micro-consensus SynCon DNA vaccine approach with the goal of breaking tolerance and increasing vaccine immune potency. This approach induced new, neo-antigen-like responses that were superior to those induced by native WT1 DNA immunogens for driving T cell immunity and breaking tolerance. Non-human primates (NHPs) vaccinated with SynCon WT1 antigens elicited immune responses against native rhesus WT1 peptides. When delivered by electroporation (EP) in mice, SynCon-based WT1 constructs elicited strong CD4 and CD8 T cell responses (including IFN-γ, CD107a, and TNF-α) to both native and consensus peptides. In addition, SynCon WT1 vaccine-induced antibodies recognized native WT1 in vitro. Vaccination with the SynCon WT1 immunogens was capable of slowing tumor growth in therapeutic models in vivo. These data support the further study of synthetic consensus DNA vaccines for breaking tolerance to important germline antigens.
Breaking tolerance to tumor-associated self-antigens is a major challenge for cancer immune therapy. Here, Walters et al. report a novel DNA vaccine design strategy using consensus sequences to help break tolerance and induce a neo-antigen-like response to the germline antigen WT1. |
| doi_str_mv | 10.1016/j.ymthe.2017.01.022 |
| format | Article |
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Breaking tolerance to tumor-associated self-antigens is a major challenge for cancer immune therapy. Here, Walters et al. report a novel DNA vaccine design strategy using consensus sequences to help break tolerance and induce a neo-antigen-like response to the germline antigen WT1.</description><identifier>ISSN: 1525-0016</identifier><identifier>EISSN: 1525-0024</identifier><identifier>DOI: 10.1016/j.ymthe.2017.01.022</identifier><identifier>PMID: 28237837</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Amino Acid Sequence ; Animal models ; Animals ; Antibodies - immunology ; Antigen (tumor-associated) ; Antigens ; Antigens, Neoplasm - immunology ; Autoantigens ; Cancer ; Cancer Vaccines - immunology ; CD4 antigen ; CD8 antigen ; Cell Line, Tumor ; Cytokines - metabolism ; Deoxyribonucleic acid ; Disease Models, Animal ; DNA ; DNA damage ; DNA vaccines ; Electroporation ; Epitopes, T-Lymphocyte - immunology ; Female ; Gene Expression ; Growth factors ; Humans ; Immune Tolerance ; Immunity ; Immunodominant Epitopes - chemistry ; Immunodominant Epitopes - immunology ; Immunological tolerance ; Leukemia ; Lymphocyte Subsets - immunology ; Lymphocyte Subsets - metabolism ; Lymphocytes ; Lymphocytes T ; Macaca mulatta ; Male ; Mesothelioma ; Mice ; Mutation ; neo-antigen ; Neoplasms - immunology ; Neoplasms - mortality ; Neoplasms - pathology ; Neoplasms - therapy ; Original ; Patients ; Peptides ; Peptides - immunology ; Pharmaceutical industry ; Proteins ; Stock options ; Studies ; T cell receptors ; Tumor necrosis factor-α ; Tumors ; Vaccination ; Vaccines ; Vaccines, DNA - immunology ; WT1 ; WT1 Proteins - immunology ; γ-Interferon</subject><ispartof>Molecular therapy, 2017-04, Vol.25 (4), p.976-988</ispartof><rights>2017 The American Society of Gene and Cell Therapy</rights><rights>Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.</rights><rights>2017. The American Society of Gene and Cell Therapy</rights><rights>2017 The American Society of Gene and Cell Therapy. 2017 The American Society of Gene and Cell Therapy</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c487t-92837922ad7100fba3b09edab2401c0a91a78ae9d35b55f1fc994147c9326c6e3</citedby><cites>FETCH-LOGICAL-c487t-92837922ad7100fba3b09edab2401c0a91a78ae9d35b55f1fc994147c9326c6e3</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/PMC5383632/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2198005242?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793,64385,64387,64389,72469</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28237837$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Walters, Jewell N.</creatorcontrib><creatorcontrib>Ferraro, Bernadette</creatorcontrib><creatorcontrib>Duperret, Elizabeth K.</creatorcontrib><creatorcontrib>Kraynyak, Kimberly A.</creatorcontrib><creatorcontrib>Chu, Jaemi</creatorcontrib><creatorcontrib>Saint-Fleur, Ashley</creatorcontrib><creatorcontrib>Yan, Jian</creatorcontrib><creatorcontrib>Levitsky, Hy</creatorcontrib><creatorcontrib>Khan, Amir S.</creatorcontrib><creatorcontrib>Sardesai, Niranjan Y.</creatorcontrib><creatorcontrib>Weiner, David B.</creatorcontrib><title>A Novel DNA Vaccine Platform Enhances Neo-antigen-like T Cell Responses against WT1 to Break Tolerance and Induce Anti-tumor Immunity</title><title>Molecular therapy</title><addtitle>Mol Ther</addtitle><description>Tumor-associated antigens have emerged as important immunotherapeutic targets in the fight against cancer. Germline tumor antigens, such as WT1, Wilms’ tumor gene 1, are overexpressed in many human malignancies but have low expression in somatic tissues. Recent vaccination approaches to target WT1 have been hampered by poor in vivo immune potency, likely due to the conserved self-antigen nature of WT1. In this study, we use a novel synthetic micro-consensus SynCon DNA vaccine approach with the goal of breaking tolerance and increasing vaccine immune potency. This approach induced new, neo-antigen-like responses that were superior to those induced by native WT1 DNA immunogens for driving T cell immunity and breaking tolerance. Non-human primates (NHPs) vaccinated with SynCon WT1 antigens elicited immune responses against native rhesus WT1 peptides. When delivered by electroporation (EP) in mice, SynCon-based WT1 constructs elicited strong CD4 and CD8 T cell responses (including IFN-γ, CD107a, and TNF-α) to both native and consensus peptides. In addition, SynCon WT1 vaccine-induced antibodies recognized native WT1 in vitro. Vaccination with the SynCon WT1 immunogens was capable of slowing tumor growth in therapeutic models in vivo. These data support the further study of synthetic consensus DNA vaccines for breaking tolerance to important germline antigens.
Breaking tolerance to tumor-associated self-antigens is a major challenge for cancer immune therapy. Here, Walters et al. report a novel DNA vaccine design strategy using consensus sequences to help break tolerance and induce a neo-antigen-like response to the germline antigen WT1.</description><subject>Amino Acid Sequence</subject><subject>Animal models</subject><subject>Animals</subject><subject>Antibodies - immunology</subject><subject>Antigen (tumor-associated)</subject><subject>Antigens</subject><subject>Antigens, Neoplasm - immunology</subject><subject>Autoantigens</subject><subject>Cancer</subject><subject>Cancer Vaccines - immunology</subject><subject>CD4 antigen</subject><subject>CD8 antigen</subject><subject>Cell Line, Tumor</subject><subject>Cytokines - metabolism</subject><subject>Deoxyribonucleic acid</subject><subject>Disease Models, Animal</subject><subject>DNA</subject><subject>DNA damage</subject><subject>DNA vaccines</subject><subject>Electroporation</subject><subject>Epitopes, T-Lymphocyte - immunology</subject><subject>Female</subject><subject>Gene Expression</subject><subject>Growth factors</subject><subject>Humans</subject><subject>Immune Tolerance</subject><subject>Immunity</subject><subject>Immunodominant Epitopes - 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immunology</topic><topic>Antigen (tumor-associated)</topic><topic>Antigens</topic><topic>Antigens, Neoplasm - immunology</topic><topic>Autoantigens</topic><topic>Cancer</topic><topic>Cancer Vaccines - immunology</topic><topic>CD4 antigen</topic><topic>CD8 antigen</topic><topic>Cell Line, Tumor</topic><topic>Cytokines - metabolism</topic><topic>Deoxyribonucleic acid</topic><topic>Disease Models, Animal</topic><topic>DNA</topic><topic>DNA damage</topic><topic>DNA vaccines</topic><topic>Electroporation</topic><topic>Epitopes, T-Lymphocyte - immunology</topic><topic>Female</topic><topic>Gene Expression</topic><topic>Growth factors</topic><topic>Humans</topic><topic>Immune Tolerance</topic><topic>Immunity</topic><topic>Immunodominant Epitopes - chemistry</topic><topic>Immunodominant Epitopes - immunology</topic><topic>Immunological tolerance</topic><topic>Leukemia</topic><topic>Lymphocyte Subsets - immunology</topic><topic>Lymphocyte Subsets - metabolism</topic><topic>Lymphocytes</topic><topic>Lymphocytes T</topic><topic>Macaca mulatta</topic><topic>Male</topic><topic>Mesothelioma</topic><topic>Mice</topic><topic>Mutation</topic><topic>neo-antigen</topic><topic>Neoplasms - immunology</topic><topic>Neoplasms - mortality</topic><topic>Neoplasms - pathology</topic><topic>Neoplasms - therapy</topic><topic>Original</topic><topic>Patients</topic><topic>Peptides</topic><topic>Peptides - immunology</topic><topic>Pharmaceutical industry</topic><topic>Proteins</topic><topic>Stock options</topic><topic>Studies</topic><topic>T cell receptors</topic><topic>Tumor necrosis factor-α</topic><topic>Tumors</topic><topic>Vaccination</topic><topic>Vaccines</topic><topic>Vaccines, DNA - immunology</topic><topic>WT1</topic><topic>WT1 Proteins - immunology</topic><topic>γ-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Walters, Jewell N.</creatorcontrib><creatorcontrib>Ferraro, Bernadette</creatorcontrib><creatorcontrib>Duperret, Elizabeth K.</creatorcontrib><creatorcontrib>Kraynyak, Kimberly A.</creatorcontrib><creatorcontrib>Chu, Jaemi</creatorcontrib><creatorcontrib>Saint-Fleur, Ashley</creatorcontrib><creatorcontrib>Yan, Jian</creatorcontrib><creatorcontrib>Levitsky, Hy</creatorcontrib><creatorcontrib>Khan, Amir S.</creatorcontrib><creatorcontrib>Sardesai, Niranjan Y.</creatorcontrib><creatorcontrib>Weiner, David B.</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>Walters, Jewell N.</au><au>Ferraro, Bernadette</au><au>Duperret, Elizabeth K.</au><au>Kraynyak, Kimberly A.</au><au>Chu, Jaemi</au><au>Saint-Fleur, Ashley</au><au>Yan, Jian</au><au>Levitsky, Hy</au><au>Khan, Amir S.</au><au>Sardesai, Niranjan Y.</au><au>Weiner, David B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A Novel DNA Vaccine Platform Enhances Neo-antigen-like T Cell Responses against WT1 to Break Tolerance and Induce Anti-tumor Immunity</atitle><jtitle>Molecular therapy</jtitle><addtitle>Mol Ther</addtitle><date>2017-04-05</date><risdate>2017</risdate><volume>25</volume><issue>4</issue><spage>976</spage><epage>988</epage><pages>976-988</pages><issn>1525-0016</issn><eissn>1525-0024</eissn><abstract>Tumor-associated antigens have emerged as important immunotherapeutic targets in the fight against cancer. Germline tumor antigens, such as WT1, Wilms’ tumor gene 1, are overexpressed in many human malignancies but have low expression in somatic tissues. Recent vaccination approaches to target WT1 have been hampered by poor in vivo immune potency, likely due to the conserved self-antigen nature of WT1. In this study, we use a novel synthetic micro-consensus SynCon DNA vaccine approach with the goal of breaking tolerance and increasing vaccine immune potency. This approach induced new, neo-antigen-like responses that were superior to those induced by native WT1 DNA immunogens for driving T cell immunity and breaking tolerance. Non-human primates (NHPs) vaccinated with SynCon WT1 antigens elicited immune responses against native rhesus WT1 peptides. When delivered by electroporation (EP) in mice, SynCon-based WT1 constructs elicited strong CD4 and CD8 T cell responses (including IFN-γ, CD107a, and TNF-α) to both native and consensus peptides. In addition, SynCon WT1 vaccine-induced antibodies recognized native WT1 in vitro. Vaccination with the SynCon WT1 immunogens was capable of slowing tumor growth in therapeutic models in vivo. These data support the further study of synthetic consensus DNA vaccines for breaking tolerance to important germline antigens.
Breaking tolerance to tumor-associated self-antigens is a major challenge for cancer immune therapy. Here, Walters et al. report a novel DNA vaccine design strategy using consensus sequences to help break tolerance and induce a neo-antigen-like response to the germline antigen WT1.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>28237837</pmid><doi>10.1016/j.ymthe.2017.01.022</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Molecular therapy, 2017-04, Vol.25 (4), p.976-988 |
| issn | 1525-0016 1525-0024 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5383632 |
| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; ProQuest Central UK/Ireland; PubMed Central; Alma/SFX Local Collection |
| subjects | Amino Acid Sequence Animal models Animals Antibodies - immunology Antigen (tumor-associated) Antigens Antigens, Neoplasm - immunology Autoantigens Cancer Cancer Vaccines - immunology CD4 antigen CD8 antigen Cell Line, Tumor Cytokines - metabolism Deoxyribonucleic acid Disease Models, Animal DNA DNA damage DNA vaccines Electroporation Epitopes, T-Lymphocyte - immunology Female Gene Expression Growth factors Humans Immune Tolerance Immunity Immunodominant Epitopes - chemistry Immunodominant Epitopes - immunology Immunological tolerance Leukemia Lymphocyte Subsets - immunology Lymphocyte Subsets - metabolism Lymphocytes Lymphocytes T Macaca mulatta Male Mesothelioma Mice Mutation neo-antigen Neoplasms - immunology Neoplasms - mortality Neoplasms - pathology Neoplasms - therapy Original Patients Peptides Peptides - immunology Pharmaceutical industry Proteins Stock options Studies T cell receptors Tumor necrosis factor-α Tumors Vaccination Vaccines Vaccines, DNA - immunology WT1 WT1 Proteins - immunology γ-Interferon |
| title | A Novel DNA Vaccine Platform Enhances Neo-antigen-like T Cell Responses against WT1 to Break Tolerance and Induce Anti-tumor Immunity |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-03T12%3A53%3A11IST&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=A%20Novel%20DNA%20Vaccine%20Platform%20Enhances%20Neo-antigen-like%20T%20Cell%20Responses%20against%20WT1%20to%20Break%20Tolerance%20and%20Induce%20Anti-tumor%20Immunity&rft.jtitle=Molecular%20therapy&rft.au=Walters,%20Jewell%20N.&rft.date=2017-04-05&rft.volume=25&rft.issue=4&rft.spage=976&rft.epage=988&rft.pages=976-988&rft.issn=1525-0016&rft.eissn=1525-0024&rft_id=info:doi/10.1016/j.ymthe.2017.01.022&rft_dat=%3Cproquest_pubme%3E2198005242%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=2198005242&rft_id=info:pmid/28237837&rft_els_id=S1525001617300576&rfr_iscdi=true |