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ul.cart a.cart-contents, #navigation .cart-contents #navigation ul.rss, #navigation ul.nav-search, #navigation ul.nav-search a { font: 14px/1.2em Helvetica, Arial, sans-serif;color:#666666; } #navigation ul.rss li a:before, #navigation ul.nav-search a.search-contents:before { color:#666666;} #navigation ul.nav li ul, #navigation ul.cart > li > ul > div { border: 0px solid #dbdbdb; } #navigation ul.nav > li:hover > ul { left: 0; } #navigation ul.nav > li { border-right: 0px solid #dbdbdb; }#navigation ul.nav > li:hover > ul { left: 0; } #navigation { box-shadow: none; -moz-box-shadow: none; -webkit-box-shadow: none; }#navigation ul li:first-child, #navigation ul li:first-child a { border-radius:0px 0 0 0px; -moz-border-radius:0px 0 0 0px; -webkit-border-radius:0px 0 0 0px; } #navigation {border-top:0px solid #dbdbdb;border-bottom:0px solid #dbdbdb;border-left:0px solid #dbdbdb;border-right:0px solid #dbdbdb;border-radius:0px; -moz-border-radius:0px; -webkit-border-radius:0px;} #top ul.nav li a { font:thin 12px/1.6em Helvetica, Arial, sans-serif;color:#ddd; } } #footer, #footer p { font:300 13px/1.4em 'Lato', arial, sans-serif;color:#ffffff; } #footer {border-top:0px solid #dbdbdb;border-bottom:0px solid ;border-left:0px solid ;border-right:0px solid ;border-radius:0px; -moz-border-radius:0px; -webkit-border-radius:0px;} .magazine #loopedSlider .content h2.title a { font:normal 24px/1em 'Lato', arial, sans-serif;color:#555555; } .wooslider-theme-magazine .slide-title a { font:normal 24px/1em 'Lato', arial, sans-serif;color:#555555; } .magazine #loopedSlider .content .excerpt p { font:normal 14px/1.5em 'Lato', arial, sans-serif;color:#555555; } .wooslider-theme-magazine .slide-content p, .wooslider-theme-magazine .slide-excerpt p { font:normal 14px/1.5em 'Lato', arial, sans-serif;color:#555555; } .magazine .block .post .title a {font:normal 18px/1.2em 'Lato', arial, sans-serif;color:#555555; } #loopedSlider.business-slider .content h2 { font:bold 24px/1em Arial, sans-serif;color:#ffffff; } #loopedSlider.business-slider .content h2.title a { font:bold 24px/1em Arial, sans-serif;color:#ffffff; } .wooslider-theme-business .has-featured-image .slide-title { font:bold 24px/1em Arial, sans-serif;color:#ffffff; } .wooslider-theme-business .has-featured-image .slide-title a { font:bold 24px/1em Arial, sans-serif;color:#ffffff; } #wrapper #loopedSlider.business-slider .content p { font:thin 13px/1.5em Arial, sans-serif;color:#cccccc; } .wooslider-theme-business .has-featured-image .slide-content p { font:thin 13px/1.5em Arial, sans-serif;color:#cccccc; } .wooslider-theme-business .has-featured-image .slide-excerpt p { font:thin 13px/1.5em Arial, sans-serif;color:#cccccc; } .archive_header { font:bold 18px/1em 'Lato', arial, sans-serif;color:#222222; } .archive_header {border-bottom:1px solid #e6e6e6;} </style>  <link rel="shortcut icon" href="https://web.archive.org/web/20210320060827im_/https://tron-mainz.de/de/wp-content/uploads/sites/9/2017/03/tron-favicon.png"/>  <link href="https://web.archive.org/web/20210320060827cs_/https://tron-mainz.de/de/wp-content/gdprpatron/hts/tron-mainz.de/de/wp_content/themes/canvas/functions/css/shortcodes_css.css" rel="stylesheet" type="text/css"/>  <link href="https://web.archive.org/web/20210320060827cs_/https://tron-mainz.de/de/wp-content/gdprpatron/hts/tron-mainz.de/de/wp_content/themes/canvas/custom_css.css" rel="stylesheet" type="text/css"/>  <meta name="generator" content="Canvas 5.9.19"/> <meta name="generator" content="WooFramework 6.2.7"/>  <link href="https://web.archive.org/web/20210320060827cs_/https://tron-mainz.de/de/wp-content/gdprpatron/hts/fonts.googleapis.com/css_family_Lato_3A100_2C147212186.css" rel="stylesheet" type="text/css"/> <meta name="generator" content="Powered by WPBakery Page Builder - drag and drop page builder for WordPress."/> <style type="text/css" id="woo-header-css"> #logo .site-title a { color: #ffffff; } </style> <style> @media only screen and ( min-width: 768px ) { #nav-container { -moz-box-shadow: 0px 0px 0px #515151 !important; -webkit-box-shadow: 0px 0px 0px #515151 !important; box-shadow: 0px 0px 0px #515151 !important; } .primary-nav-container, .side-nav, #navigation ul.nav li a, #navigation ul.rss a, #navigation ul.cart a.cart-contents, #navigation .cart-contents #navigation ul.rss, #navigation ul.nav-search, #navigation ul.nav-search a { font-family: Lato ; font-size: 1.1em ; font-style: normal ; font-weight: 700; color : #164679 !important; } #navigation > section > .primary-nav-container ul.nav > .current-menu-item > a, #navigation > section > .primary-nav-container ul.nav > .current-menu-parent > a { color: #be3026 !important ; } #navigation > section > .primary-nav-container ul.nav > .menu-item.current-menu-item { background-color: #ffffff ; } #navigation > section > .primary-nav-container ul.nav > .current-menu-item > a { background-color: transparent ; } #navigation > section > .primary-nav-container ul.nav > .menu-item { background-color: #ffffff ; } #navigation .side-nav > ul > li > a { background-color: #ffffff !important ;color: #164679 !important; } #navigation > section > .primary-nav-container ul.nav > .menu-item > a { background-color: transparent ; } #navigation ul.nav > li:hover > a, #navigation .side-nav > ul > li:hover > a { color: #9b0000 !important; background: !important; } #navigation .side-nav > ul > li > a:before { color: inherit !important; } #navigation > section > .primary-nav-container ul.nav > .menu-item > a { text-shadow: inherit !important; } #navigation > section > .primary-nav-container ul.nav > .menu-item { } #navigation > section > .primary-nav-container ul.nav > .menu-item:hover { } #navigation > section > .primary-nav-container ul.nav { display: inline-block; float: none !important ; } #navigation > section > .primary-nav-container ul.nav > li.menu-item { display: inline-block !important; float: none !important; vertical-align: middle !important; } #navigation > section { height: auto; text-align: right !important ; } #navigation > section > .primary-nav-container ul.nav { display: inline-block; float: none !important ; } #navigation > section > .primary-nav-container ul.nav > li.menu-item { display: inline-block !important; float: none !important; vertical-align: middle !important; } #navigation > section { height: 42px; text-align: right !important ; } #navigation > section > .primary-nav-container ul.nav > .menu-item > a { padding-top: px !important ; padding-bottom: px !important ; padding-right: px !important ; padding-left: px !important ; } #navigation > section > .primary-nav-container ul.nav > .menu-item { margin-top: px !important ; margin-bottom: px !important ; margin-right: px !important ; margin-left: px !important ; } #navigation > section > .primary-nav-container ul.nav > .menu-item, #navigation > section > .primary-nav-container ul.nav > .menu-item > a { border-radius: !important ; } #navigation > section > .primary-nav-container ul.nav > .menu-item { border: none !important; } #navigation > section > .primary-nav-container ul.nav > .menu-item:hover, #navigation > section > .primary-nav-container ul.nav > .menu-item.hover { border-color: !important; } #navigation > section > .primary-nav-container ul.nav > .menu-item.current-menu-item { border-color: #be3026 !important; } #navigation > section > .primary-nav-container ul.nav > .menu-item- > a { font-family: ; font-size: px ; font-style: normal ; font-weight: 400; color : !important; } #navigation > section > .primary-nav-container ul.nav > .menu-item-.current-menu-item > a { color: !important ; } #navigation > section > .primary-nav-container ul.nav > .menu-item-.current-menu-item { background-color: ; } #navigation > section > .primary-nav-container ul.nav > .menu-item-:hover > a { color: !important ; background-color: !important ; } #navigation > section > .primary-nav-container ul.nav > .menu-item- { background-color: ; } #navigation > section > .primary-nav-container ul.nav > .menu-item- { } #navigation > section > .primary-nav-container ul.nav > .menu-item- > a { padding: px px !important ; } #navigation > section > .primary-nav-container ul.nav > .menu-item- { margin: px px !important ; } #navigation > section > .primary-nav-container ul.nav > .menu-item- { border-radius: !important ; border-top: px solid ; border-bottom: px solid ; border-left: px solid ; border-right: px solid ; } #navigation > section > .primary-nav-container ul.nav > .menu-item-.current-menu-item:hover, #navigation > section > .primary-nav-container ul.nav > .menu-item-:hover { border-top: px solid ; border-bottom: px solid ; border-left: px solid ; border-right: px solid ; } #navigation > section > .primary-nav-container ul.nav > .menu-item-.current-menu-item { border-top: px solid ; border-bottom: px solid ; border-left: px solid ; border-right: px solid ; } #navigation > section > .primary-nav-container ul.nav > .menu-item .sub-menu, #navigation > section > .primary-nav-container ul.nav > .menu-item .sub-menu > .menu-item > a, #navigation > section > .side-nav .widget_shopping_cart, #navigation ul.cart .cart_list a { font-family: ; font-size: 1em ; font-style: normal ; font-weight: 400; color : !important; } #navigation > section > .primary-nav-container ul.nav > .menu-item .sub-menu > .menu-item > a:hover, #navigation > section > .side-nav .widget_shopping_cart { text-decoration: none; } #navigation > section > .primary-nav-container ul.nav .sub-menu { text-align: left !important ; } #navigation > section > .primary-nav-container ul.nav > .menu-item .sub-menu > .menu-item { border-top: px solid ; border-bottom: px solid ; border-left: px solid ; border-right: px solid ; } #navigation > section > .primary-nav-container ul.nav > .menu-item .sub-menu > .menu-item:hover { border-top: px solid ; border-bottom: px solid ; border-left: px solid ; border-right: px solid ; } #navigation > section > .primary-nav-container ul.nav > .menu-item .sub-menu, #navigation .side-nav > .cart > li > ul, #navigation .side-nav > .nav-search > li > ul { background-color: #ffffff !important; } #navigation > section > .primary-nav-container ul.nav > .menu-item .sub-menu > .menu-item:hover > a { color: #be3026 !important; } #navigation > section > .primary-nav-container ul.nav > .menu-item .sub-menu { padding-top: 0 !important; padding-bottom: 0 !important; } #navigation > section > .primary-nav-container ul.nav .sub-menu > .menu-item > a, #navigation > section > .side-nav .widget_shopping_cart { } #navigation > section > .primary-nav-container ul.nav .sub-menu, #navigation > section > .side-nav > .cart > li > ul { } body #navigation > section > .primary-nav-container ul.nav > .menu-item .sub-menu, #navigation > section > .side-nav > .cart > li > ul { border-radius: !important ; } #navigation > section > .primary-nav-container ul.nav > .menu-item .sub-menu > .menu-item:first-child { border-radius: 0 0 !important ; } #navigation > section > .primary-nav-container ul.nav > .menu-item .sub-menu > .menu-item:last-child { border-radius: 0 0 !important ; } #navigation > section > .primary-nav-container ul.nav { display: inline-block; vertical-align: middle; } #navigation > section > .side-nav { height:100%; vertical-align: middle; float:right; } #nav-container, #navigation { background-color: #ffffff !important; } #nav-container {border: none !important;}#nav-container { -moz-border-radius: 3px !important; -webkit-border-radius: 3px !important; border-radius: 3px !important; } #navigation ul.nav li ul { width:168px; font-size:14px; }#navigation ul.nav li { line-height:1.2em; }#navigation ul .sub-menu > li:first-child, #navigation ul .sub-menu > li:first-child > a { border-radius: 0 !important; -moz-border-radius: 0 !important; -webkit-border-radius: 0 !important; } #navigation { margin-top:0;margin-bottom:0; } #nav-container { margin-top: px; margin-bottom: px; } #navigation ul.nav > li > a { } #navigation ul.nav > li > a > i { margin-right: 5px; line-height: inherit; vertical-align: middle; color: ; } #navigation ul.nav > li > a:hover > i { color: ; } #navigation ul.nav > li.current-menu-item > a > i { color: ; } #navigation ul.nav > li ul li > a { line-height: ; } #navigation ul.nav > li ul li > a > i { float: left; margin-right: 5px; line-height: inherit; color: ; text-decoration: initial; } #nav-container #navigation ul#main-nav > li:first-child { border-left: none; } #navigation { transform: initial !important; }.primary-nav-container { display: inline-block; }#navigation ul.rss li.sub-rss a i,#navigation ul.rss li.sub-email a i{display:none;}body #navigation > section > .primary-nav-container ul.nav > .menu-item > .sub-menu > .menu-item:first { border-radius: 0 !important; } #navigation #main-nav > .menu-item > .sub-menu:before { content: ''; } #navigation #main-nav { font-size: 0; } #navigation #main-nav li { font-size: 14px; } #navigation #main-nav > .menu-item.parent:after { content: ''; position: absolute; top: 100%; display: none; } #navigation #main-nav > .menu-item.parent:hover:after { content: ''; position: absolute; top: 100%; display: block; } #navigation > section { height: auto; }#navigation .side-nav > .rss { position: relative; line-height: 100%; height: 100%; } #navigation .side-nav > .rss > li { line-height: 100%; height: 100%; } #navigation .side-nav > .rss > li > a { padding-top: 0; padding-bottom: 0; line-height: 100%; height: 100%; position: relative; overflow:hidden; } #navigation .side-nav > .rss > li > a:hover { text-decoration: none; } #navigation .side-nav > ul > li > a:before { position: absolute !important; top: 50% !important; margin-top: -0.5em !important; line-height:1; } #navigation .side-nav > .cart { line-height: 100%; height: 100% } #navigation .side-nav > .cart > li { height: 100% } #navigation .side-nav > .cart > li > .cart-contents { padding-top: 0; padding-bottom: 0; line-height: 100%; height: 100%; position: relative; } @media only screen and (min-width: 980px) { #navigation .side-nav > .cart > li { display: table; } #navigation .side-nav > .cart > li > a.cart-contents { display: table-cell; vertical-align: middle; } #navigation .side-nav > .cart > li > a.cart-contents:before { position: initial !important; } } #navigation ul.cart a.cart-contents + ul { box-sizing: content-box; } #navigation .side-nav > .nav-search { line-height: 100%; height: 100% } #navigation .side-nav > .nav-search > li { height: 100% } #navigation .side-nav > .nav-search > li > .search-contents { padding-top: 0; padding-bottom: 0; line-height: 100%; height: 100%; position: relative } #navigation .side-nav > ul > li > a:before { color: #be3026 !important; } #navigation .side-nav > ul > li > a:hover:before { color: !important; } #navigation #main-nav > .menu-item > a > span { vertical-align: middle; } .side-nav ul ul input , .side-nav ul ul :before { color: !important ; } } @media only screen and ( max-width: 767px ) { #navigation ul.nav > li > a > i { display: none; } #navigation ul.nav > li ul li > a > i { display: none } } </style> <style type="text/css">/* *** NEWS BOX - WP DYNAMIC CUSTOM THEME *** */ .lcnb_wpdt_theme .lcnb_loading { background: url('https://web.archive.org/web/20210320060827im_/https://tron-mainz.de/de/wp-content/gdprpatron/hts/tron-mainz.de/de/wp_content/plugins/swift_box_wp/js/sb//img/loader_d_gif.gif') no-repeat center center transparent; } .lcnb_wpdt_theme article.lcnb_news, .lcnb_wpdt_theme .lcnb_exp_block { background-color: #ffffff; } .lcnb_wpdt_theme.lcnb_wrap.lcnb_uniblock .lcnb_inner_wrapper { border-radius: 0px; } .lcnb_wpdt_theme.lcnb_wrap.lcnb_uniblock .lcnb_news, .lcnb_wpdt_theme.lcnb_wrap.lcnb_boxed article.lcnb_news, .lcnb_wpdt_theme.lcnb_wrap.lcnb_uniblock .lcnb_exp_block { border: 0px solid #D5D5D5; -moz-transition: 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.lcnb_exp_block { border: 0px solid #D5D5D5; border-radius: 0px; box-shadow: none; } .lcnb_wpdt_theme .lcnb_title { color: #164679 !important; border-bottom: 1px solid #FFFFFF; font-weight: bold; } .lcnb_wpdt_theme .lcnb_txt, .lcnb_wpdt_theme .lcnb_exp_txt { color: #555555; } .lcnb_wpdt_theme .lcnb_txt a { color: #be3026 !important; } .lcnb_wpdt_theme .lcnb_img { background: url('https://web.archive.org/web/20210320060827im_/https://tron-mainz.de/de/wp-content/gdprpatron/hts/tron-mainz.de/de/wp_content/plugins/swift_box_wp/js/sb//img/loader_d_gif.gif') no-repeat center center transparent; } .lcnb_wpdt_theme .lcnb_social_box li { color: #164679; } /* navigation commands */ .lcnb_wpdt_theme.lcnb_has_cmd .lcnb_prev, .lcnb_wpdt_theme.lcnb_has_cmd .lcnb_next { border: 1px solid #D5D5D5; background-color: #ffffff; } .lcnb_wpdt_theme.lcnb_has_cmd .lcnb_prev:hover, .lcnb_wpdt_theme.lcnb_has_cmd .lcnb_next:hover { border-color: #C4C4C4; } .lcnb_wpdt_theme .lcnb_cmd span:before { color: #164679; } /* source logos */ .lcnb_wpdt_theme.lcnb_src_logo .lcnb_type_twitter > div { background-image: url("https://web.archive.org/web/20210320060827im_/https://tron-mainz.de/de/wp-content/gdprpatron/hts/tron-mainz.de/de/wp_content/plugins/swift_box_wp/js/sb//img/social_src_logos/dark/twitter_png.png"); } .lcnb_wpdt_theme.lcnb_src_logo .lcnb_type_rss > div { background-image: url("https://web.archive.org/web/20210320060827im_/https://tron-mainz.de/de/wp-content/gdprpatron/hts/tron-mainz.de/de/wp_content/plugins/swift_box_wp/js/sb//img/social_src_logos/dark/rss_png.png"); } .lcnb_wpdt_theme.lcnb_src_logo .lcnb_type_pinterest > div { background-image: url("https://web.archive.org/web/20210320060827im_/https://tron-mainz.de/de/wp-content/gdprpatron/hts/tron-mainz.de/de/wp_content/plugins/swift_box_wp/js/sb//img/social_src_logos/dark/pinterest_png.png"); } .lcnb_wpdt_theme.lcnb_src_logo .lcnb_type_facebook > div { background-image: 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class="side-nav"> <ul class="nav-search"> <li> <a class="search-contents" href="#"></a> <ul> <li> <div class="widget widget_search"><div class="search_main"> <form method="get" class="searchform" action="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/"> <input type="text" class="field s" name="s" value="Search..." onfocus="if (this.value == 'Search...') {this.value = '';}" onblur="if (this.value == '') {this.value = 'Search...';}"/> <button type="submit" class="fa fa-search submit" name="submit" value="Search"></button> </form> <div class="fix"></div> </div></div> </li> </ul> </li> </ul> </div> </section> <a href="#top" class="nav-close"> <i class="fa fa-times"></i> <span>Return to Content</span> </a> </nav> </div> </header> </div>  <div id="content" class="col-full"> <div id="main-sidebar-container">  <section id="main"> <article class="post-6803 page type-page status-publish hentry category-publications"> <header> <h1 class="title entry-title">2016</h1> </header> <section class="entry"> <div class="vc_row wpb_row vc_row-fluid vc_column-gap-15 mpc-row"><div class="wpb_column vc_column_container vc_col-sm-9 mpc-column" data-column-id="mpc_column-686055915b7d8a7"><div class="vc_column-inner"><div class="wpb_wrapper"> <div class="wpb_text_column wpb_content_element "> <div class="wpb_wrapper"> <p>Strenkowska M, Grzela R, Majewski M, Wnek K, Kowalska J, Lukaszewicz M, Zuberek J, Darzynkiewicz E, Kuhn AN, Sahin U, Jemielity J. (2016) <strong>Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential.</strong> <em>Nucleic Acids Res.  </em>44(20):9578-9590.<br> <a href="https://web.archive.org/web/20210320060827/https://dx.doi.org/10.1093/nar/gkw896" target="_blank" rel="noopener noreferrer">DOI;</a> <a href="https://web.archive.org/web/20210320060827/https://www.ncbi.nlm.nih.gov/pubmed/27903882" target="_blank" rel="noopener noreferrer">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim">Along with a growing interest in mRNA-based gene therapies, efforts are increasingly focused on reaching the full translational potential of mRNA, as a major obstacle for in vivo applications is sufficient expression of exogenously delivered mRNA. One method to overcome this limitation is chemically modifying the 7-methylguanosine cap at the 5′ end of mRNA (m7Gppp-RNA). We report a novel class of cap analogs designed as reagents for mRNA modification. The analogs carry a 1,2-dithiodiphosphate moiety at various positions along a tri- or tetraphosphate bridge, and thus are termed 2S analogs. These 2S analogs have high affinities for translation initiation factor 4E, and some exhibit remarkable resistance against the SpDcp1/2 decapping complex when introduced into RNA. mRNAs capped with 2S analogs combining these two features exhibit high translation efficiency in cultured human immature dendritic cells. These properties demonstrate that 2S analogs are potentially beneficial for mRNA-based therapies such as anti-cancer immunization.</div></div> <p> </p> <p>Waisman A, Hövelmeyer N, Diefenbach A, Schuppan D, Reddehase MJ, Kleinert H, Kaina B, Grabbe S, Galle PR, Theobald M, Zipp F, Sahin U, Türeci Ö, Kreiter S, Langguth P, Decker H, van Zandbergen G, Schild H. (2016) <strong>Past, present and future of immunology in Mainz.</strong> <em>Cell Immunol. </em>308:1-6.<br> <a href="https://web.archive.org/web/20210320060827/https://dx.doi.org/10.1016/j.cellimm.2016.09.001" target="_blank" rel="noopener noreferrer">DOI;</a> <a href="https://web.archive.org/web/20210320060827/https://www.ncbi.nlm.nih.gov/pubmed/27719802" target="_blank" rel="noopener noreferrer">PubMed</a></p> <p> </p> <p>Grabbe S, Haas H, Diken M, Kranz LM, Langguth P, Sahin U. (2016) <strong>Translating nanoparticulate-personalized cancer vaccines into clinical applications: case study with RNA-lipoplexes for the treatment of melanoma</strong>. <em>Nanomedicine (Lond)</em> 2016 Oct 11.<br> <a href="https://web.archive.org/web/20210320060827/https://dx.doi.org/10.2217/nnm-2016-0275" target="_blank" rel="noopener noreferrer">DOI;</a> <a href="https://web.archive.org/web/20210320060827/http://www.ncbi.nlm.nih.gov/pubmed/27700619" target="_blank" rel="noopener noreferrer">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim">The development of nucleic acid based vaccines against cancer has gained considerable momentum through the advancement of modern sequencing technologies and on novel RNA-based synthetic drug formats, which can be readily adapted following identification of every patient’s tumor-specific mutations. Furthermore, affordable and individual ‘on demand’ production of molecularly optimized vaccines should allow their application in large groups of patients. This has resulted in the therapeutic concept of an active personalized cancer vaccine, which has been brought into clinical testing. Successful trials have been performed by intranodal administration of sterile isotonic solutions of synthetic RNA vaccines. The second generation of RNA vaccines which is currently being developed encompasses intravenously injectable RNA nanoparticle formulations (lipoplexes), made up from lipid excipients, denoted RNA<sub>(LIP)</sub>. A first product that has made its way from bench to bedside is a therapeutic vaccine for intravenous administration based on a fixed set of four RNA lipoplex drug products, each encoding for one shared tumor antigen (Lipoplex Melanoma RNA Immunotherapy, ‘Lipo-MERIT’). This article describes the steps for translating these novel RNA nanomedicines into clinical trials.</div></div> <p> </p> <p>Poschke I, Faryna M, Bergmann F, Flossdorf M, Lauenstein C, Hermes J, Hinz U, Hank T, Ehrenberg R, Volkmar M, Loewer M, Glimm H, Hackert T, Sprick MR, Höfer T, Trumpp A, Halama N, Hassel JC, Strobel O, Büchler M, Sahin U, Offringa R. (2016) <strong>Identification of a tumor-reactive T-cell repertoire in the immune infiltrate of patients with resectable pancreatic ductal adenocarcinoma.</strong> <em>Oncoimmunology. </em>5(12):e124085.<br> <a href="https://web.archive.org/web/20210320060827/https://dx.doi.org/10.1080/2162402X.2016.1240859" target="_blank" rel="noopener noreferrer">DOI;</a> <a href="https://web.archive.org/web/20210320060827/https://www.ncbi.nlm.nih.gov/pubmed/28123878" target="_blank" rel="noopener noreferrer">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim">Purpose: The devastating prognosis of patients with resectable pancreatic ductal adenocarcinoma (PDA) presents an urgent need for the development of therapeutic strategies targeting disseminated tumor cells. Until now, T-cell therapy has been scarcely pursued in PDA, due to the prevailing view that it represents a poorly immunogenic tumor. Experimental design: We systematically analyzed T-cell infiltrates in tumor biopsies from 127 patients with resectable PDA by means of immunohistochemistry, flow cytometry, T-cell receptor (TCR) deep-sequencing and functional analysis of in vitro expanded T-cell cultures. Parallel studies were performed on tumor-infiltrating lymphocytes (TIL) from 44 patients with metastatic melanoma.<br> Results: Prominent T-cell infiltrates, as well as tertiary lymphoid structures harboring proliferating T-cells, were detected in the vast majority of biopsies from PDA patients. The notion that the tumor is a site of local T-cell expansion was strengthened by TCR deep-sequencing, revealing that the T-cell repertoire in the tumor is dominated by highly frequent CDR3 sequences that can be up to 10,000-fold enriched in tumor as compared to peripheral blood. In fact, TCR repertoire composition in PDA resembled that in melanoma. Moreover, in vitro expansion of TILs was equally efficient for PDA and melanoma, resulting in T-cell cultures displaying HLA class I-restricted reactivity against autologous tumor cells.<br> Conclusions: The tumor-infiltrating T-cell response in PDA shows striking similarity to that in melanoma, where adoptive T-cell therapy has significant therapeutic impact. Our findings indicate that T-cell-based therapies may be used to counter disease recurrence in patients with resectable PDA.</div></div> <p> </p> <p>Liu Y, Loewer M, Aluru S, Schmidt B. (2016)<span style="font-size: 13.3333px"> </span><strong>SNVSniffer: an integrated caller for germline and somatic single-nucleotide and indel mutations. </strong><em>BMC Syst Biol</em>. 10 Suppl 2:47.</p> <p><a href="https://web.archive.org/web/20210320060827/http://10.1186/s12918-016-0300-5">DOI</a>; <a href="https://web.archive.org/web/20210320060827/https://www.ncbi.nlm.nih.gov/pubmed/27489955">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim"> <h4>BACKGROUND:</h4> <p>Various approaches to calling single-nucleotide variants (SNVs) or insertion-or-deletion (indel) mutations have been developed based on next-generation sequencing (NGS). However, most of them are dedicated to a particular type of mutation, e.g. germline SNVs in normal cells, somatic SNVs in cancer/tumor cells, or indels only. In the literature, efficient and integrated callers for both germline and somatic SNVs/indels have not yet been extensively investigated.</p> <h4>RESULTS:</h4> <p>We present SNVSniffer, an efficient and integrated caller identifying both germline and somatic SNVs/indels from NGS data. In this algorithm, we propose the use of Bayesian probabilistic models to identify SNVs and investigate a multiple ungapped alignment approach to call indels. For germline variant calling, we model allele counts per site to follow a multinomial conditional distribution. For somatic variant calling, we rely on paired tumor-normal pairs from identical individuals and introduce a hybrid subtraction and joint sample analysis approach by modeling tumor-normal allele counts per site to follow a joint multinomial conditional distribution. A comprehensive performance evaluation has been conducted using a diversity of variant calling benchmarks. For germline variant calling, SNVSniffer demonstrates highly competitive accuracy with superior speed in comparison with the state-of-the-art FaSD, GATK and SAMtools. For somatic variant calling, our algorithm achieves comparable or even better accuracy, at fast speed, than the leading VarScan2, SomaticSniper, JointSNVMix2 and MuTect.</p> <h4>CONCLUSIONS:</h4> <p>SNVSniffers demonstrates the feasibility to develop integrated solutions to fast and efficient identification of germline and somatic variants. Nonetheless, accurate discovery of genetic variations is critical yet challenging, and still requires substantially more research efforts being devoted. SNVSniffer and synthetic samples are publicly available at http://snvsniffer.sourceforge.net.</p></div></div> <p> </p> <p>Selmi A, Vascotto F, Kautz-Neu K, Türeci Ö, Sahin U, von Stebut E, Diken M, Kreiter S. (2016) <strong>Uptake of synthetic naked RNA by skin-resident dendritic cells via macropinocytosis allows antigen expression and induction of T-cell responses in mice. </strong><em>Cancer Immunol Immunother</em> 65(9):1075-83.<br> <a href="https://web.archive.org/web/20210320060827/http://dx.doi.org/10.1007/s00262-016-1869-7" target="_blank" rel="noopener noreferrer">DOI;</a> <a href="https://web.archive.org/web/20210320060827/http://www.ncbi.nlm.nih.gov/pubmed/27422115" target="_blank" rel="noopener noreferrer">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim">Intradermal administration of antigen-encoding RNA has entered clinical testing for cancer vaccination. However, insight into the underlying mechanism of RNA uptake, translation and antigen presentation is still limited. Utilizing pharmacologically optimized naked RNA, the dose-response kinetics revealed a rise in reporter signal with increasing RNA amounts and a prolonged RNA translation of reporter protein up to 30 days after intradermal injection. Dendritic cells (DCs) in the dermis were shown to engulf RNA, and the signal arising from the reporter RNA was significantly diminished after DC depletion. Macropinocytosis was relevant for intradermal RNA uptake and translation in vitro and in vivo. By combining intradermal RNA vaccination and inhibition of macropinocytosis, we show that effective priming of antigen-specific CD8<sup>+</sup> T-cells also relies on this uptake mechanism. This report demonstrates that direct antigen translation by dermal DCs after intradermal naked RNA vaccination is relevant for efficient priming of antigen-specific T-cells.</div></div> <p> </p> <p>Kranz LM, Diken M, Haas H, Kreiter S, Loquai C, Reuter KC, Meng M, Fritz D, Vascotto F, Hefesha H, Grunwitz C, Vormehr M, Hüsemann Y, Selmi A, Kuhn AN, Buck J, Derhovanessian E, Rae R, Attig S, Diekmann J, Jabulowsky RA, Heesch S, Hassel J, Langguth P, Grabbe S, Huber C, Türeci Ö, Sahin U. (2016) <strong>Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. </strong><em>Nature.</em> 534(7607):396-401.<br> <a href="https://web.archive.org/web/20210320060827/http://dx.doi.org/10.1038/nature18300" target="_blank" rel="noopener noreferrer">DOI;</a> <a href="https://web.archive.org/web/20210320060827/http://www.ncbi.nlm.nih.gov/pubmed/27281205" target="_blank" rel="noopener noreferrer">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim"><br> Lymphoid organs, in which antigen presenting cells (APCs) are in close proximity to T cells, are the ideal microenvironment for efficient priming and amplification of T-cell responses. However, the systemic delivery of vaccine antigens into dendritic cells (DCs) is hampered by various technical challenges. Here we show that DCs can be targeted precisely and effectively in vivo using intravenously administered RNA-lipoplexes (RNA-LPX) based on well-known lipid carriers by optimally adjusting net charge, without the need for functionalization of particles with molecular ligands. The LPX protects RNA from extracellular ribonucleases and mediates its efficient uptake and expression of the encoded antigen by DC populations and macrophages in various lymphoid compartments. RNA-LPX triggers interferon-α (IFNα) release by plasmacytoid DCs and macrophages. Consequently, DC maturation in situ and inflammatory immune mechanisms reminiscent of those in the early systemic phase of viral infection are activated. We show that RNA-LPX encoding viral or mutant neo-antigens or endogenous self-antigens induce strong effector and memory T-cell responses, and mediate potent IFNα-dependent rejection of progressive tumours. A phase I dose-escalation trial testing RNA-LPX that encode shared tumour antigens is ongoing. In the first three melanoma patients treated at a low-dose level, IFNα and strong antigen-specific T-cell responses were induced, supporting the identified mode of action and potency. As any polypeptide-based antigen can be encoded as RNA, RNA-LPX represent a universally applicable vaccine class for systemic DC targeting and synchronized induction of both highly potent adaptive as well as type-I-IFN-mediated innate immune mechanisms for cancer immunotherapy.</div></div> <p> </p> <p>Kreiter S, Diken M, Selmi A, Petschenka J, Türeci Ö, Sahin U. (2016) <strong>FLT3 Ligand as a Molecular Adjuvant for Naked RNA Vaccines. </strong><em>Methods Mol Biol.</em> 1428:163-75.<br> <a href="https://web.archive.org/web/20210320060827/http://dx.doi.org/10.1007/978-1-4939-3625-0_11" target="_blank" rel="noopener noreferrer">DOI;</a> <a href="https://web.archive.org/web/20210320060827/http://www.ncbi.nlm.nih.gov/pubmed/27236799" target="_blank" rel="noopener noreferrer">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim"><br> Intranodal immunization with antigen-encoding naked mRNA has proven to be an efficacious and safe approach to induce antitumor immunity. Thanks to its unique characteristics, mRNA can act not only as a source for antigen but also as an adjuvant for activation of the immune system. The search for additional adjuvants that can be combined with mRNA to further improve the potency of the immunization revealed Fms-like tyrosine kinase 3 (FLT3) ligand as a potent candidate. Systemic administration of the dendritic cell-activating FLT3 ligand prior to or along with mRNA immunization-enhanced priming and expansion of antigen-specific CD8(+) T cells in lymphoid organs, T-cell homing into melanoma tumors, and therapeutic activity of the intranodally administered mRNA. Both compounds demonstrate a successful combination in terms of boosting the immune response. This chapter describes methods for intranodal immunization with naked mRNA by co-administration of FLT3 ligand, which leads to strong synergistic effects.</div></div> <p> </p> <p>Alrefai H, Muhammad K, Rudolf R, Pham DA, Klein-Hessling S, Patra AK, Avots A, Bukur V, Sahin U, Tenzer S, Goebeler M, Kerstan A, Serfling E. (2016) <strong>NFATc1 supports imiquimod-induced skin inflammation by suppressing IL-10 synthesis in B cells. </strong><em>Nat Commun.</em> 7:11724.<br> <a href="https://web.archive.org/web/20210320060827/http://dx.doi.org/10.1038/ncomms11724" target="_blank" rel="noopener noreferrer">DOI;</a> <a href="https://web.archive.org/web/20210320060827/http://www.ncbi.nlm.nih.gov/pubmed/27222343" target="_blank" rel="noopener noreferrer">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim"><br> Epicutaneous application of Aldara cream containing the TLR7 agonist imiquimod (IMQ) to mice induces skin inflammation that exhibits many aspects of psoriasis, an inflammatory human skin disease. Here we show that mice depleted of B cells or bearing interleukin (IL)-10-deficient B cells show a fulminant inflammation upon IMQ exposure, whereas ablation of NFATc1 in B cells results in a suppression of Aldara-induced inflammation. In vitro, IMQ induces the proliferation and IL-10 expression by B cells that is blocked by BCR signals inducing NFATc1. By binding to HDAC1, a transcriptional repressor, and to an intronic site of the Il10 gene, NFATc1 suppresses IL-10 expression that dampens the production of tumour necrosis factor-α and IL-17 by T cells. These data indicate a close link between NFATc1 and IL-10 expression in B cells and suggest NFATc1 and, in particular, its inducible short isoform, NFATc1/αA, as a potential target to treat human psoriasis.</div></div> <p> </p> <p>Wirtz RM, Sihto H, Isola J, Heikkilä P, Kellokumpu-Lehtinen PL, Auvinen P, Turpeenniemi-Hujanen T, Jyrkkiö S, Lakis S, Schlombs K, Laible M, Weber S, Eidt S, Sahin U, Joensuu H. (2016) <strong>Biological subtyping of early breast cancer: a study comparing RT-qPCR with immunohistochemistry.</strong> <em>Breast Cancer Res Treat.</em> 157(3):437-46.<br> <a href="https://web.archive.org/web/20210320060827/http://dx.doi.org/10.1007/s10549-016-3835-7" target="_blank" rel="noopener noreferrer">DOI;</a> <a href="https://web.archive.org/web/20210320060827/http://www.ncbi.nlm.nih.gov/pubmed/27220750" target="_blank" rel="noopener noreferrer">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim"><br> The biological subtype of breast cancer influences the selection of systemic therapy. Distinction between luminal A and B cancers depends on consistent assessment of Ki-67, but substantial intra-observer and inter-observer variability exists when immunohistochemistry (IHC) is used. We compared RT-qPCR with IHC in the assessment of Ki-67 and other standard factors used in breast cancer subtyping. RNA was extracted from archival breast tumour tissue of 769 women randomly assigned to the FinHer trial. Cancer ESR1, PGR, ERBB2 and MKI67 mRNA content was quantitated with an RT-qPCR assay. Local pathologists assessed ER, PgR and Ki-67 expression using IHC. HER2 amplification was identified with chromogenic in situ hybridization (CISH) centrally. The results were correlated with distant disease-free survival (DDFS) and overall survival (OS). qPCR-based and IHC-based assessments of ER and PgR showed good concordance. Both low tumour MKI67 mRNA (RT-qPCR) and Ki-67 protein (IHC) levels were prognostic for favourable DDFS [hazard ratio (HR) 0.42, 95 % CI 0.25-0.71, P = 0.001; and HR 0.56, 0.37-0.84, P = 0.005, respectively] and OS. In multivariable analyses, cancer MKI67 mRNA content had independent influence on DDFS (adjusted HR 0.51, 95 % CI 0.29-0.89, P = 0.019) while Ki-67 protein expression had not any influence (P = 0.266) whereas both assessments influenced independently OS. Luminal B patients treated with docetaxel-FEC had more favourable DDFS and OS than those treated with vinorelbine-FEC when the subtype was defined by RT-qPCR (for DDFS, HR 0.52, 95 % CI 0.29-0.94, P = 0.031), but not when defined using IHC. Breast cancer subtypes approximated with RT-qPCR and IHC show good concordance, but cancer MKI67 mRNA content correlated slightly better with DDFS than Ki-67 expression. The findings based on MKI67 mRNA content suggest that patients with luminal B cancer benefit more from docetaxel-FEC than from vinorelbine-FEC.</div></div> <p> </p> <p>McCann KJ, Mander A, Cazaly A, Chudley L, Stasakova J, Thirdborough SM, King A, Lloyd-Evans P, Buxton E, Edwards C, Halford S, Bateman A, O’Callaghan A, Clive S, Anthoney A, Jodrell DI, Weinschenk T, Simon P, Sahin U, Thomas GJ, Stevenson FK, Ottensmeier CH. (2016) <strong>Targeting Carcinoembryonic Antigen with DNA Vaccination: On-Target Adverse Events Link with Immunological and Clinical Outcomes.</strong> <em>Clinical Cancer Research.</em> 22(19):4827-4836.<br> <a href="https://web.archive.org/web/20210320060827/http://dx.doi.org/10.1158/1078-0432.CCR-15-2507" target="_blank" rel="noopener noreferrer">DOI;</a> <a href="https://web.archive.org/web/20210320060827/http://www.ncbi.nlm.nih.gov/pubmed/27091407" target="_blank" rel="noopener noreferrer">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim"><br> <strong>PURPOSE:</strong><br> We have clinically evaluated a DNA fusion vaccine to target the HLA-A*0201 binding peptide CAP-1 from carcinoembryonic antigen (CEA<sub>605-613</sub>) linked to an immunostimulatory domain (DOM) from fragment C of tetanus toxin Experimental Design: Twenty-seven patients with CEA-expressing carcinomas were recruited: 15 patients with measurable disease (Arm-I) and 12 patients without radiological evidence of disease (Arm-II). Six intramuscular vaccinations of naked DNA (1mg/dose) were administered up to week 12. Clinical and immunological follow-up was to week 64 or clinical/radiological disease.<br> <strong>RESULTS:</strong><br> DOM-specific immune responses demonstrated successful vaccine delivery. All patients without measurable disease compared to 60% with advanced disease responded immunologically, while 58% and 20% expanded anti-CAP-1 CD8<sup>+</sup> T-cells, respectively. CAP-1-specific T-cells were only detectable in the blood post-vaccination, but could also be identified in previously resected cancer tissue. The gastrointestinal adverse event diarrhea was reported by 48% of patients and linked to more frequent decreases in CEA (p<0.001) and improved global immunological responses (anti-DOM responses of greater magnitude (p<0.001), frequency (p=0.004) and duration) compared to patients without diarrhea. In advanced disease patients, decreases in CEA were associated with better overall survival (HR=0.14, p=0.017). CAP-1 peptide was detectable on MHC class I of normal bowel mucosa and primary colorectal cancer tissue by mass-spectrometry, offering a mechanistic explanation for diarrhea through CD8<sup>+</sup> T-cell attack.<br> <strong>CONCLUSIONS:</strong><br> Our data suggest that DNA vaccination is able to overcome peripheral tolerance in normal and tumor tissue and warrants testing in combination studies, for example, by vaccinating in parallel to treatment with an anti-PD1 antibody.</div></div> <p> </p> <p>Türeci Ö, Vormehr M, Diken M, Kreiter S, Huber C, <span class="highlight">Sahin U. (2016)</span> <strong>Targeting the Heterogeneity of Cancer with Individualized Neoepitope Vaccines.</strong> <em>Clinical Cancer Research.</em>  22(8):1885-96.<br> <a href="https://web.archive.org/web/20210320060827/http://dx.doi.org/10.1158/1078-0432.CCR-15-1509" target="_blank" rel="noopener noreferrer">DOI;</a> <a href="https://web.archive.org/web/20210320060827/http://www.ncbi.nlm.nih.gov/pubmed/27084742" target="_blank" rel="noopener noreferrer">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim">Somatic mutations binding to the patient’s MHC and recognized by autologous T cells (neoepitopes) are ideal cancer vaccine targets. They combine a favorable safety profile due to a lack of expression in healthy tissues with a high likelihood of immunogenicity, as T cells recognizing neoepitopes are not shaped by central immune tolerance. Proteins mutated in cancer (neoantigens) shared by patients have been explored as vaccine targets for many years. Shared (“public”) mutations, however, are rare, as the vast majority of cancer mutations in a given tumor are unique for the individual patient. Recently, the novel concept of truly individualized cancer vaccination emerged, which exploits the vast source of patient-specific “private” mutations. Concurrence of scientific advances and technological breakthroughs enables the rapid, cost-efficient, and comprehensive mapping of the “mutanome,” which is the entirety of somatic mutations in an individual tumor, and the rational selection of neoepitopes. How to transform tumor mutanome data to actionable knowledge for tailoring individualized vaccines “on demand” has become a novel research field with paradigm-shifting potential. This review gives an overview with particular focus on the clinical development of such vaccines.</div></div> <p> </p> <p>Knies D, Klobuch S, Xue SA, Birtel M, Echchannaoui H, Yildiz O, Omokoko T, Guillaume P, Romero P, Stauss H, Sahin U, Herr W, Theobald M, Thomas S, Voss RH. (2016) <strong>An optimized single chain TCR scaffold relying on the assembly with the native CD3-complex prevents residual mispairing with endogenous TCRs in human T-cells.</strong> <em>Oncotarget.</em> 7(16):21199-221.<br> <a href="https://web.archive.org/web/20210320060827/http://dx.doi.org/10.18632/oncotarget.8385" target="_blank" rel="noopener noreferrer">DOI;</a> <a href="https://web.archive.org/web/20210320060827/http://www.ncbi.nlm.nih.gov/pubmed/27028870" target="_blank" rel="noopener noreferrer">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim">Immunotherapy of cancer envisions the adoptive transfer of T-cells genetically engineered with tumor-specific heterodimeric α/β T-cell receptors (TCRα/β). However, potential mispairing of introduced TCRα/β-chains with endogenous β/α-ones may evoke unpredictable autoimmune reactivities. A novel single chain (sc)TCR format relies on the fusion of the Vα-Linker-Vβ-fragment to the TCR Cβ-domain and coexpression of the TCR Cα-domain capable of recruiting the natural CD3-complex for full and hence, native T-cell signaling. Here, we tested whether such a gp100(280-288)- or p53(264-272) tumor antigen-specific scTCR is still prone to mispairing with TCRα. In a human Jurkat-76 T-cell line lacking endogenous TCRs, surface expression and function of a scTCR could be reconstituted by any cointroduced TCRα-chain indicating mispairing to take place on a molecular basis. In contrast, transduction into human TCRα/β-positive T-cells revealed that mispairing is largely reduced. Competition experiments in Jurkat-76 confirmed the preference of dcTCR to selfpair and to spare scTCR. This also allowed for the generation of dc/scTCR-modified cytomegalovirus/tumor antigen-bispecific T-cells to augment T-cell activation in CMV-infected tumor patients. Residual mispairing was prevented by strenghtening the Vα-Li-Vβ-fragment through the design of a novel disulfide bond between a Vα- and a linker-resident residue close to Vβ. Multimer-stainings, and cytotoxicity-, IFNγ-secretion-, and CFSE-proliferation-assays, the latter towards dendritic cells endogenously processing RNA-electroporated gp100 antigen proved the absence of hybrid scTCR/TCRα-formation without impairing avidity of scTCR/Cα in T-cells. Moreover, a fragile cytomegalovirus pp65(495-503)-specific scTCR modified this way acquired enhanced cytotoxicity. Thus, optimized scTCR/Cα inhibits residual TCR mispairing to accomplish safe adoptive immunotherapy for bulk endogenous TCRα/β-positive T-cells.</div></div> <p> </p> <p>Kreiter S, Diken M, Pascolo S, Nair SK, Thielemans KM, Geall A. (2016) <strong>The RNA Vaccination Therapy: Advances in an Emerging Field</strong>. <em>J Immunol Res. </em><br> <a href="https://web.archive.org/web/20210320060827/http://dx.doi.org/10.1155/2016/9703914" target="_blank" rel="noopener noreferrer">DOI;</a> <a href="https://web.archive.org/web/20210320060827/http://www.ncbi.nlm.nih.gov/pubmed/27019856" target="_blank" rel="noopener noreferrer">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim">No abstract available</div></div> <p> </p> <p>Kranz LM, Birtel M, Krienke C, Grunwitz C, Petschenka J, Reuter KC, van de Roemer N, Vascotto F, Vormehr M, Kreiter S, Diken M. (2016) <strong>CIMT 2015: The right patient for the right therapy – Report on the 13th annual meeting of the Association for Cancer Immunotherapy</strong>. <em>Human Vaccines & Immunotherapeutics.</em>  12:213-221.<br> <a href="https://web.archive.org/web/20210320060827/http://doi.org/10.1080/21645515.2015.1068485" target="_blank" rel="noopener noreferrer">DOI;</a> <a href="https://web.archive.org/web/20210320060827/http://www.ncbi.nlm.nih.gov/pubmed/26186022" target="_blank" rel="noopener noreferrer">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim">The 13th Annual Meeting of the Association for Cancer Immunotherapy (CIMT) brought together more than 800 scientists in Mainz, Germany, from May 11–13, 2015, to present and discuss current research on various fields of cancer immunotherapy. Special focus was set on personalized approaches, and independent of the specific therapeutic strategy, the exploitation of mutated neoantigens predominated all sessions – in line with the motto of this year’s meeting, “The right patient for the right therapy.”</div></div> <p> </p> <p>Omokoko TA, Luxemburger U, Bardissi S, Simon P, Utsch M, Breitkreuz A, Türeci Ö, <span class="highlight">Sahin U. (2016)</span> <strong>Luciferase mRNA Transfection of Antigen Presenting Cells Permits Sensitive Nonradioactive Measurement of Cellular and Humoral Cytotoxicity.</strong> <em>J Immunol Res.</em>  2016:9540975.<br> <a href="https://web.archive.org/web/20210320060827/http://dx.doi.org/10.1155/2016/9540975" target="_blank" rel="noopener noreferrer">DOI;</a> <a href="https://web.archive.org/web/20210320060827/http://www.ncbi.nlm.nih.gov/pubmed/27057556" target="_blank" rel="noopener noreferrer">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim">Immunotherapy is rapidly evolving as an effective treatment option for many cancers. With the emerging fields of cancer vaccines and adoptive cell transfer therapies, there is an increasing demand for high-throughput in vitro cytotoxicity assays that efficiently analyze immune effector functions. The gold standard (51)Cr-release assay is very accurate but has the major disadvantage of being radioactive. We reveal the development of a versatile and nonradioactive firefly luciferase in vitro transcribed (IVT) RNA-based assay. Demonstrating high efficiency, consistency, and excellent target cell viability, our optimized luciferase IVT RNA is used to transfect dividing and nondividing primary antigen presenting cells. Together with the long-lasting expression and minimal background, the direct measurement of intracellular luciferase activity of living cells allows for the monitoring of killing kinetics and displays paramount sensitivity. The ability to cotransfect the IVT RNA of the luciferase reporter and the antigen of interest into the antigen presenting cells and its simple read-out procedure render the assay high-throughput in nature. Results generated were comparable to the (51)Cr release and further confirmed the assay’s ability to measure antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. The assay’s combined simplicity, practicality, and efficiency tailor it for the analysis of antigen-specific cellular and humoral effector functions during the development of novel immunotherapies.</div></div> <p> </p> <p>Wagner M, Jung J, Koslowski M, Türeci Ö, Tiwari VK, Sahin U. (2016) <strong>Chromatin Immunoprecipitation Assay to Identify Genomic Binding Sites of Regulatory Factors</strong>. <em>Methods in Molecular Biology (Clifton, N.J.)</em> <strong>1366</strong>:53-65.<br> <a href="https://web.archive.org/web/20210320060827/http://doi.org/10.1007/978-1-4939-3127-9_6">DOI;</a> <a href="https://web.archive.org/web/20210320060827/http://www.ncbi.nlm.nih.gov/pubmed/26585127">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim">No abstract available.</div></div> <p> </p> <p>Kloke BP, Kreiter S, Vormehr M, Diken M, Kuhn AN, <span class="highlight">Sahin U. (2016)</span> <strong>Actively personalized cancer vaccines–the step into clinical application.</strong> <em>Pharmazie</em> 2016, 1:43-7.<br> <a href="https://web.archive.org/web/20210320060827/http://www.ncbi.nlm.nih.gov/pubmed/26867352" target="_blank" rel="noopener noreferrer">PubMed</a></p> <div class="su-spoiler su-spoiler-style-default su-spoiler-icon-plus su-spoiler-closed" data-scroll-offset="0" data-anchor-in-url="no"><div class="su-spoiler-title" tabindex="0" role="button"><span class="su-spoiler-icon"></span>Show abstract</div><div class="su-spoiler-content su-u-clearfix su-u-trim">Cancer vaccine development enters a new phase of innovation based on the development of modern sequencing technologies and novel RNA-based synthetic drug formats which enable the analysis and therapeutic targeting of every patient’s tumor genome. By applying and combining these innovations, we have brought the concept of “actively personalized cancer vaccines” to clinical testing. Synthetic RNA is used as the drug format, allowing affordable, individual “on demand” manufacturing of tumor-optimized vaccines.</div></div> </div> </div> </div></div></div><div class="wpb_column vc_column_container vc_col-sm-3 mpc-column"><div class="vc_column-inner"><div class="wpb_wrapper"> <div class="vc_grid-container-wrapper vc_clearfix"> <div class="vc_grid-container vc_clearfix wpb_content_element vc_basic_grid" data-initial-loading-animation="fadeIn" data-vc-grid-settings="{"page_id":6803,"style":"all","action":"vc_get_vc_grid_data","shortcode_id":"1496994012594-b4927bf6-e4bc-2","tag":"vc_basic_grid"}" data-vc-request="https://tron-mainz.de/de/wp-admin/admin-ajax.php" data-vc-post-id="6803" data-vc-public-nonce="660a59436e"> <style data-type="vc_shortcodes-custom-css">.vc_custom_1484316837418{background-color: #164679 !important;background-position: center !important;background-repeat: no-repeat !important;background-size: cover 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center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2017-2/" class="vc_gitem-link" title="2017">2017</a></h3></div></div></div></div></div></div></div><div class="vc_clearfix"></div></div><div class="vc_grid-item vc_clearfix vc_col-sm-12"><div class="vc_grid-item-mini vc_clearfix "><div class="vc_gitem-animated-block vc_gitem-animate vc_gitem-animate-none" data-vc-animation="none"><div class="vc_gitem-zone vc_gitem-zone-a vc_custom_1484316837418 vc-gitem-zone-height-mode-auto vc-gitem-zone-height-mode-auto-16-9 vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2015-2/" title="2015" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920202167 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2015-2/" class="vc_gitem-link" title="2015">2015</a></h3></div></div></div></div></div><div class="vc_gitem-zone vc_gitem-zone-b vc_custom_1484317192348 vc-gitem-zone-height-mode-auto vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2015-2/" title="2015" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920211292 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2015-2/" class="vc_gitem-link" title="2015">2015</a></h3></div></div></div></div></div></div></div><div class="vc_clearfix"></div></div><div class="vc_grid-item vc_clearfix vc_col-sm-12"><div class="vc_grid-item-mini vc_clearfix "><div class="vc_gitem-animated-block vc_gitem-animate vc_gitem-animate-none" data-vc-animation="none"><div class="vc_gitem-zone vc_gitem-zone-a vc_custom_1484316837418 vc-gitem-zone-height-mode-auto vc-gitem-zone-height-mode-auto-16-9 vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2014-2/" title="2014" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920202167 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2014-2/" class="vc_gitem-link" title="2014">2014</a></h3></div></div></div></div></div><div class="vc_gitem-zone vc_gitem-zone-b vc_custom_1484317192348 vc-gitem-zone-height-mode-auto vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2014-2/" title="2014" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920211292 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2014-2/" class="vc_gitem-link" title="2014">2014</a></h3></div></div></div></div></div></div></div><div class="vc_clearfix"></div></div><div class="vc_grid-item vc_clearfix vc_col-sm-12"><div class="vc_grid-item-mini vc_clearfix "><div class="vc_gitem-animated-block vc_gitem-animate vc_gitem-animate-none" data-vc-animation="none"><div class="vc_gitem-zone vc_gitem-zone-a vc_custom_1484316837418 vc-gitem-zone-height-mode-auto vc-gitem-zone-height-mode-auto-16-9 vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/publications/2013-2/" title="2013" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920202167 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/publications/2013-2/" class="vc_gitem-link" title="2013">2013</a></h3></div></div></div></div></div><div class="vc_gitem-zone vc_gitem-zone-b vc_custom_1484317192348 vc-gitem-zone-height-mode-auto vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/publications/2013-2/" title="2013" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920211292 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/publications/2013-2/" class="vc_gitem-link" title="2013">2013</a></h3></div></div></div></div></div></div></div><div class="vc_clearfix"></div></div><div class="vc_grid-item vc_clearfix vc_col-sm-12"><div class="vc_grid-item-mini vc_clearfix "><div class="vc_gitem-animated-block vc_gitem-animate vc_gitem-animate-none" data-vc-animation="none"><div class="vc_gitem-zone vc_gitem-zone-a vc_custom_1484316837418 vc-gitem-zone-height-mode-auto vc-gitem-zone-height-mode-auto-16-9 vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/publications/2012-2/" title="2012" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920202167 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/publications/2012-2/" class="vc_gitem-link" title="2012">2012</a></h3></div></div></div></div></div><div class="vc_gitem-zone vc_gitem-zone-b vc_custom_1484317192348 vc-gitem-zone-height-mode-auto vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/publications/2012-2/" title="2012" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920211292 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/publications/2012-2/" class="vc_gitem-link" title="2012">2012</a></h3></div></div></div></div></div></div></div><div class="vc_clearfix"></div></div><div class="vc_grid-item vc_clearfix vc_col-sm-12"><div class="vc_grid-item-mini vc_clearfix "><div class="vc_gitem-animated-block vc_gitem-animate vc_gitem-animate-none" data-vc-animation="none"><div class="vc_gitem-zone vc_gitem-zone-a vc_custom_1484316837418 vc-gitem-zone-height-mode-auto vc-gitem-zone-height-mode-auto-16-9 vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/publications/2011-2/" title="2011" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920202167 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/publications/2011-2/" class="vc_gitem-link" title="2011">2011</a></h3></div></div></div></div></div><div class="vc_gitem-zone vc_gitem-zone-b vc_custom_1484317192348 vc-gitem-zone-height-mode-auto vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/publications/2011-2/" title="2011" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920211292 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/publications/2011-2/" class="vc_gitem-link" title="2011">2011</a></h3></div></div></div></div></div></div></div><div class="vc_clearfix"></div></div><div class="vc_grid-item vc_clearfix vc_col-sm-12"><div class="vc_grid-item-mini vc_clearfix "><div class="vc_gitem-animated-block vc_gitem-animate vc_gitem-animate-none" data-vc-animation="none"><div class="vc_gitem-zone vc_gitem-zone-a vc_custom_1484316837418 vc-gitem-zone-height-mode-auto vc-gitem-zone-height-mode-auto-16-9 vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/publications/2010-2/" title="2010" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920202167 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/publications/2010-2/" class="vc_gitem-link" title="2010">2010</a></h3></div></div></div></div></div><div class="vc_gitem-zone vc_gitem-zone-b vc_custom_1484317192348 vc-gitem-zone-height-mode-auto vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/publications/2010-2/" title="2010" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920211292 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/publications/2010-2/" class="vc_gitem-link" title="2010">2010</a></h3></div></div></div></div></div></div></div><div class="vc_clearfix"></div></div><div class="vc_grid-item vc_clearfix vc_col-sm-12"><div class="vc_grid-item-mini vc_clearfix "><div class="vc_gitem-animated-block vc_gitem-animate vc_gitem-animate-none" data-vc-animation="none"><div class="vc_gitem-zone vc_gitem-zone-a vc_custom_1484316837418 vc-gitem-zone-height-mode-auto vc-gitem-zone-height-mode-auto-16-9 vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2018-2/" title="2018" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920202167 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2018-2/" class="vc_gitem-link" title="2018">2018</a></h3></div></div></div></div></div><div class="vc_gitem-zone vc_gitem-zone-b vc_custom_1484317192348 vc-gitem-zone-height-mode-auto vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2018-2/" title="2018" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920211292 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2018-2/" class="vc_gitem-link" title="2018">2018</a></h3></div></div></div></div></div></div></div><div class="vc_clearfix"></div></div><div class="vc_grid-item vc_clearfix vc_col-sm-12"><div class="vc_grid-item-mini vc_clearfix "><div class="vc_gitem-animated-block vc_gitem-animate vc_gitem-animate-none" data-vc-animation="none"><div class="vc_gitem-zone vc_gitem-zone-a vc_custom_1484316837418 vc-gitem-zone-height-mode-auto vc-gitem-zone-height-mode-auto-16-9 vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2019-2/" title="2019" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920202167 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2019-2/" class="vc_gitem-link" title="2019">2019</a></h3></div></div></div></div></div><div class="vc_gitem-zone vc_gitem-zone-b vc_custom_1484317192348 vc-gitem-zone-height-mode-auto vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2019-2/" title="2019" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920211292 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2019-2/" class="vc_gitem-link" title="2019">2019</a></h3></div></div></div></div></div></div></div><div class="vc_clearfix"></div></div><div class="vc_grid-item vc_clearfix vc_col-sm-12"><div class="vc_grid-item-mini vc_clearfix "><div class="vc_gitem-animated-block vc_gitem-animate vc_gitem-animate-none" data-vc-animation="none"><div class="vc_gitem-zone vc_gitem-zone-a vc_custom_1484316837418 vc-gitem-zone-height-mode-auto vc-gitem-zone-height-mode-auto-16-9 vc_gitem-is-link"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2020-2/" title="2020" class="vc_gitem-link vc-zone-link"></a><div class="vc_gitem-zone-mini"><div class="vc_gitem_row vc_row vc_gitem-row-position-middle"><div class="vc_col-sm-12 vc_gitem-col vc_gitem-col-align-"><div class="vc_custom_heading sidegrid vc_custom_1486920202167 vc_gitem-post-data vc_gitem-post-data-source-post_title"><h3 style="color: #ffffff;text-align: center;font-family:Lato;font-weight:700;font-style:normal"><a href="https://web.archive.org/web/20210320060827/https://tron-mainz.de/de/2020-2/" class="vc_gitem-link" title="2020">2020</a></h3></div></div></div></div></div><div class="vc_gitem-zone vc_gitem-zone-b vc_custom_1484317192348 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