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<!DOCTYPE html> <html lang="en" class="grade-c"> <head> <title>Vaccine-based immunotherapeutic approaches to gliomas and beyond | Nature Reviews Neurology</title> <link rel="alternate" type="application/rss+xml" href="https://www.nature.com/nrneurol.rss"/> <script id="save-data-connection-testing"> function hasConnection() { return navigator.connection || navigator.mozConnection || navigator.webkitConnection || navigator.msConnection; } function createLink(src) { var preloadLink = document.createElement("link"); preloadLink.rel = "preload"; preloadLink.href = src; preloadLink.as = "font"; preloadLink.type = "font/woff2"; preloadLink.crossOrigin = ""; document.head.insertBefore(preloadLink, document.head.firstChild); } var connectionDetail = { saveDataEnabled: false, slowConnection: false }; var connection = hasConnection(); if (connection) { connectionDetail.saveDataEnabled = connection.saveData; if (/\slow-2g|2g/.test(connection.effectiveType)) { connectionDetail.slowConnection = true; } } if (!(connectionDetail.saveDataEnabled || connectionDetail.slowConnection)) { createLink("/static/fonts/HardingText-Regular-Web-cecd90984f.woff2"); } else { document.documentElement.classList.add('save-data'); } </script> <link rel="preconnect" href="https://cmp.nature.com" crossorigin> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="applicable-device" content="pc,mobile"> <meta name="viewport" content="width=device-width,initial-scale=1.0,maximum-scale=5,user-scalable=yes"> <meta name="360-site-verification" content="5a2dc4ab3fcb9b0393241ffbbb490480" /> <script data-test="dataLayer"> window.dataLayer = [{"content":{"category":{"contentType":"review article","legacy":{"webtrendsPrimaryArticleType":"reviews","webtrendsSubjectTerms":"brain;cns-cancer;therapeutics;vaccines","webtrendsContentCategory":null,"webtrendsContentCollection":null,"webtrendsContentGroup":"Nature Reviews Neurology","webtrendsContentGroupType":null,"webtrendsContentSubGroup":"Review Article","status":null}},"article":{"doi":"10.1038/nrneurol.2017.64"},"attributes":{"cms":null,"deliveryPlatform":"oscar","copyright":{"open":false,"legacy":{"webtrendsLicenceType":null}}},"contentInfo":{"authors":["Michael Weller","Patrick Roth","Matthias Preusser","Wolfgang Wick","David A. 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Although efficacy remains unproven for the vaccines in clinical development, Weller and colleagues highlight promising strategies for antagonizing glioma-associated immunosuppression and boosting immune responses in vaccinated patients. Ultimately, such approaches might help to control the growth of human gliomas. Astrocytic and oligodendroglial gliomas are intrinsic brain tumours characterized by infiltrative growth and resistance to classic cancer therapies, which renders them inevitably lethal. Glioblastoma, the most common type of glioma, also exhibits neoangiogenesis and profound immunosuppressive properties. Accordingly, strategies to revert glioma-associated immunosuppression and promote tumour-directed immune responses have been extensively explored in rodent models and in large clinical trials of tumour immunotherapy. This Review describes vaccination approaches investigated for the treatment of glioma. Several strategies have reached phase III clinical trials, including vaccines targeting epidermal growth factor receptor variant III, and the use of either immunogenic peptides or tumour lysates to stimulate autologous dendritic cells. Other approaches in early phases of clinical development employ multipeptide vaccines such as IMA-950, cytomegalovirus-derived peptides, or tumour-derived peptides such as heat shock protein-96 peptide complexes and the Arg132His mutant form of isocitrate dehydrogenase. 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Sampson","affiliation":[{"name":"Duke University Medical Center","address":{"name":"Department of Neurosurgery, Duke University Medical Center, Durham, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"}],"isAccessibleForFree":true,"@type":"ScholarlyArticle"},"@context":"https://schema.org","@type":"WebPage"}</script> <link rel="canonical" href="https://www.nature.com/articles/nrneurol.2017.64"> <meta name="journal_id" content="41582"/> <meta name="dc.title" content="Vaccine-based immunotherapeutic approaches to gliomas and beyond"/> <meta name="dc.source" content="Nature Reviews Neurology 2017 13:6"/> <meta name="dc.format" content="text/html"/> <meta name="dc.publisher" content="Nature Publishing Group"/> <meta name="dc.date" content="2017-05-12"/> <meta name="dc.type" content="ReviewPaper"/> <meta name="dc.language" content="En"/> <meta name="dc.copyright" content="2017 Springer Nature Limited"/> <meta name="dc.rights" content="2017 Springer Nature Limited"/> <meta name="dc.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="dc.description" content="This Review presents an overview of vaccine-based immunotherapies for human glioma. 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<header> <ul class="c-article-identifiers" data-test="article-identifier"> <li class="c-article-identifiers__item" data-test="article-category">Review Article</li> <li class="c-article-identifiers__item">Published: <time datetime="2017-05-12">12 May 2017</time></li> </ul> <h1 class="c-article-title" data-test="article-title" data-article-title="">Vaccine-based immunotherapeutic approaches to gliomas and beyond</h1> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Michael-Weller-Aff1" data-author-popup="auth-Michael-Weller-Aff1" data-author-search="Weller, Michael" data-corresp-id="c1">Michael Weller<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Patrick-Roth-Aff1" data-author-popup="auth-Patrick-Roth-Aff1" data-author-search="Roth, Patrick">Patrick Roth</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Matthias-Preusser-Aff2" data-author-popup="auth-Matthias-Preusser-Aff2" data-author-search="Preusser, Matthias">Matthias Preusser</a><sup class="u-js-hide"><a href="#Aff2">2</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Wolfgang-Wick-Aff3" data-author-popup="auth-Wolfgang-Wick-Aff3" data-author-search="Wick, Wolfgang">Wolfgang Wick</a><sup class="u-js-hide"><a href="#Aff3">3</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-David_A_-Reardon-Aff4" data-author-popup="auth-David_A_-Reardon-Aff4" data-author-search="Reardon, David A.">David A. Reardon</a><sup class="u-js-hide"><a href="#Aff4">4</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Michael-Platten-Aff3-Aff5" data-author-popup="auth-Michael-Platten-Aff3-Aff5" data-author-search="Platten, Michael">Michael Platten</a><sup class="u-js-hide"><a href="#Aff3">3</a>,<a href="#Aff5">5</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 7 authors for this article" title="Show all 7 authors for this article">…</li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-John_H_-Sampson-Aff6" data-author-popup="auth-John_H_-Sampson-Aff6" data-author-search="Sampson, John H.">John H. Sampson</a><sup class="u-js-hide"><a href="#Aff6">6</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/nrneurol" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Nature Reviews Neurology</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 13</b>, <span class="u-visually-hidden">pages </span>363–374 (<span data-test="article-publication-year">2017</span>)<a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">7767 <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">13 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/nrneurol.2017.64/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </header> <div class="u-js-hide" data-component="article-subject-links"> <h3 class="c-article__sub-heading">Subjects</h3> <ul class="c-article-subject-list"> <li class="c-article-subject-list__subject"><a href="/subjects/brain" data-track="click" data-track-action="view subject" data-track-label="link">Brain</a></li><li class="c-article-subject-list__subject"><a href="/subjects/cns-cancer" data-track="click" data-track-action="view subject" data-track-label="link">CNS cancer</a></li><li class="c-article-subject-list__subject"><a href="/subjects/therapeutics" data-track="click" data-track-action="view subject" data-track-label="link">Therapeutics</a></li><li class="c-article-subject-list__subject"><a href="/subjects/vaccines" data-track="click" data-track-action="view subject" data-track-label="link">Vaccines</a></li> </ul> </div> </div> <div class="c-article-body"> <section aria-labelledby="Abs1" data-title="Key Points" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Key Points</h2><div class="c-article-section__content" id="Abs1-content"> <ul class="u-list-style-bullet"> <li> <p>Glioblastoma is the paradigm of tumour-associated immunosuppression</p> </li> <li> <p>Several glioma-specific peptide vaccines, with or without dendritic cell support, are in late clinical development</p> </li> <li> <p>Vaccines can be combined with agents that nonspecifically boost immune responses, such as immune checkpoint inhibitors or TGFβ pathway inhibitors</p> </li> <li> <p>Standardization of clinical trial conduct might facilitate progress in this challenging field of oncology</p> </li> </ul> </div></div></section><section aria-labelledby="Abs3" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs3-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs3">Abstract</h2><div class="c-article-section__content" id="Abs3-content"><p>Astrocytic and oligodendroglial gliomas are intrinsic brain tumours characterized by infiltrative growth and resistance to classic cancer therapies, which renders them inevitably lethal. Glioblastoma, the most common type of glioma, also exhibits neoangiogenesis and profound immunosuppressive properties. Accordingly, strategies to revert glioma-associated immunosuppression and promote tumour-directed immune responses have been extensively explored in rodent models and in large clinical trials of tumour immunotherapy. This Review describes vaccination approaches investigated for the treatment of glioma. Several strategies have reached phase III clinical trials, including vaccines targeting epidermal growth factor receptor variant III, and the use of either immunogenic peptides or tumour lysates to stimulate autologous dendritic cells. Other approaches in early phases of clinical development employ multipeptide vaccines such as IMA-950, cytomegalovirus-derived peptides, or tumour-derived peptides such as heat shock protein-96 peptide complexes and the Arg132His mutant form of isocitrate dehydrogenase. However, some preclinical trial data suggest that addition of immunomodulatory reagents such as immune checkpoint inhibitors, transforming growth factor-β inhibitors, signal transducer and activator of transcription 3 inhibitors, or modifiers of tryptophan metabolism could augment the therapeutic activity of vaccination and overcome glioma-associated immunosuppression.</p></div></div></section> <noscript> </noscript> <section aria-labelledby="inline-recommendations" data-title="Inline Recommendations" class="c-article-recommendations" data-track-component="inline-recommendations"> <h3 class="c-article-recommendations-title" id="inline-recommendations">Similar content being viewed by others</h3> <div class="c-article-recommendations-list"> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41698-024-00717-4/MediaObjects/41698_2024_717_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41698-024-00717-4?fromPaywallRec=false" data-track="select_recommendations_1" data-track-context="inline recommendations" data-track-action="click recommendations inline - 1" data-track-label="10.1038/s41698-024-00717-4">Therapeutic approaches to modulate the immune microenvironment in gliomas </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">23 October 2024</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41586-021-03363-z/MediaObjects/41586_2021_3363_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41586-021-03363-z?fromPaywallRec=false" data-track="select_recommendations_2" data-track-context="inline recommendations" data-track-action="click recommendations inline - 2" data-track-label="10.1038/s41586-021-03363-z">A vaccine targeting mutant IDH1 in newly diagnosed glioma </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">24 March 2021</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41568-019-0224-7/MediaObjects/41568_2019_224_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://www.nature.com/articles/s41568-019-0224-7?fromPaywallRec=false" data-track="select_recommendations_3" data-track-context="inline recommendations" data-track-action="click recommendations inline - 3" data-track-label="10.1038/s41568-019-0224-7">Brain immunology and immunotherapy in brain tumours </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__date">05 December 2019</span> </div> </div> </article> </div> </div> </section> <script> window.dataLayer = window.dataLayer || []; window.dataLayer.push({ recommendations: { recommender: 'semantic', model: 'specter', policy_id: 'NA', timestamp: 1732641813, embedded_user: 'null' } }); </script> <div class="main-content"> <section data-title="Main"><div class="c-article-section" id="Sec1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec1">Main</h2><div class="c-article-section__content" id="Sec1-content"><p>Throughout the past century, pivotal research issues in oncology have included the extent to which immunosuppression is a risk factor for the development of cancer, and the extent to which cancer induces immunosuppression. Accordingly, immunosuppression has been extensively studied in brain tumours such as glioma, which commonly kills affected patients by locally destructive growth rather than by systemic metastasis. Multiple cellular interactions and pathways that might potentially mediate glioma-associated immunosuppression have been identified<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Nduom, E. K., Weller, M. & Heimberger, A. B. Immunosuppressive mechanisms in glioblastoma. Neuro Oncol. 17 (Suppl. 7), vii9–vii14 (2015)." href="/articles/nrneurol.2017.64#ref-CR1" id="ref-link-section-d70610963e575">1</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Mangani, D., Weller, M. & Roth, P. The network of immunosuppressive pathways in glioblastoma. Biochem. Pharmacol. 130, 1–9 (2017)." href="/articles/nrneurol.2017.64#ref-CR2" id="ref-link-section-d70610963e578">2</a></sup> (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nrneurol.2017.64#Fig1">Fig. 1</a>).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-1" data-title="Glioma-associated pathways of local and systemic immunosuppression."><figure><figcaption><b id="Fig1" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 1: Glioma-associated pathways of local and systemic immunosuppression.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/nrneurol.2017.64/figures/1" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnrneurol.2017.64/MediaObjects/41582_2017_Article_BFnrneurol201764_Fig1_HTML.jpg?as=webp"><img aria-describedby="Fig1" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnrneurol.2017.64/MediaObjects/41582_2017_Article_BFnrneurol201764_Fig1_HTML.jpg" alt="figure 1" loading="lazy" width="685" height="395"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-1-desc"><p>Membrane-bound and soluble mediators of glioma-associated immunosuppression both attract and promote the expansion of populations of immunosuppressive cells, and interfere with the generation of antitumour immunity at the T cell–antigen-presenting cell (APC) interface. CTLA4, cytotoxic T cell antigen 4; GDF15, growth and differentiation factor 15; IDO, indoleamine 2,3-dioxygenase; Kyn, kynurenine; LLT1, lectin-like transcript 1; MDSC, myeloid-derived suppressor cell; NK, natural killer; PD1, programmed cell death protein 1; PDL1, programmed cell death 1 ligand 1; PGE, prostaglandin E2, STAT3, signal transducer and activator of transcription 3; TDO, tryptophan 2,3-dioxygenase; TGFβ, transforming growth factor β; T<sub>reg</sub> cell, regulatory T cell; Trp, tryptophan.</p><p> <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nrneurol.2017.64#MOESM103">PowerPoint slide</a> </p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/nrneurol.2017.64/figures/1" data-track-dest="link:Figure1 Full size image" aria-label="Full size image figure 1" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Several decades ago, researchers also recognized that gliomas in the brain promote systemic immunosuppression to a certain degree<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Roszman, T., Elliott, L. & Brooks, W. Modulation of T-cell function by gliomas. Immunol. Today 12, 370–374 (1991)." href="/articles/nrneurol.2017.64#ref-CR3" id="ref-link-section-d70610963e616">3</a></sup>, although such immunosuppression is not associated with an increased risk of opportunistic infections. Tumours growing in essentially immunocompromised environments such as the brain would not be expected to derive an advantage from inducing additional immunosuppression. Moreover, even glioblastomas — the most common and most malignant gliomas — seem to be largely incapable of seeding outside the CNS<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Schweitzer, T., Vince, G. H., Herbold, C., Roosen, K. & Tonn, J. C. Extraneural metastases of primary brain tumors. J. Neurooncol. 53, 107–114 (2001)." href="/articles/nrneurol.2017.64#ref-CR4" id="ref-link-section-d70610963e620">4</a></sup>. This observation has been attributed, at least partially, to immune defence mechanisms that operate only outside the brain. However, experimental or clinical data supporting the existence of efficient anti-glioma immune responses in the periphery, but not inside the CNS, has remained very challenging to obtain.</p><p>One of the most remarkable features of gliomas is the observation that these tumours develop much more frequently in elderly individuals (aged ≥60 years), and that outcome is substantially worse in this age group than in younger individuals<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Ostrom, Q. T. et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008–2012. Neuro Oncol. 17 (Suppl. 4), iv1–iv62 (2015)." href="/articles/nrneurol.2017.64#ref-CR5" id="ref-link-section-d70610963e627">5</a></sup>. Molecular profiling has enabled the characterization of distinct subtypes of glioblastoma that are most common in children and adults up to 40 years of age<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Sturm, D. et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22, 425–437 (2012)." href="/articles/nrneurol.2017.64#ref-CR6" id="ref-link-section-d70610963e631">6</a></sup>. In the population of adults with glioblastoma, the small prognostically favourable subgroup of tumours with isocitrate dehydrogenase (<i>IDH</i>) gene mutations is virtually absent in patients aged ≥60 years<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Hartmann, C. et al. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol. 120, 707–718 (2010)." href="/articles/nrneurol.2017.64#ref-CR7" id="ref-link-section-d70610963e638">7</a></sup>. By contrast, high-throughput studies of the three most common <i>IDH</i> wild-type glioblastoma subtypes in adults (namely, receptor tyrosine kinase (RTK) 1, RTK 2, and mesenchymal) show few differences at the genomic, transcriptomic or epigenetic level between tumours from elderly individuals (>65 years) and those from younger patients<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Sturm, D. et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22, 425–437 (2012)." href="/articles/nrneurol.2017.64#ref-CR6" id="ref-link-section-d70610963e646">6</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Bozdag, S. et al. Age-specific signatures of glioblastoma at the genomic, genetic, and epigenetic levels. PLoS ONE 8, e62982 (2013)." href="/articles/nrneurol.2017.64#ref-CR8" id="ref-link-section-d70610963e649">8</a></sup>. These data suggest that the status of the host, rather than the molecular make-up of the tumour, might to a large extent determine the outcome of these types of cancer.</p><p>In summary, the clinical relevance of glioma-associated immunosuppression remains debated. Nevertheless, the past 5 years have seen the clinical translation of various cancer immunotherapies, some of which are glioma-specific. Several of these strategies involve innovative vaccination strategies that are challenging, in terms of both conceptional design and logistical conduct, to implement in the clinic (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nrneurol.2017.64#Fig2">Fig. 2</a>). Immediate conceptual challenges include the choice of antigen to be targeted, the selection of patients on the basis of tumour biomarkers and immune markers (such as HLA status), and the timing of assessment of the status of such markers. Further conceptual challenges involve the integration of immunotherapy into post-surgical treatment schedules (such as tapering of corticosteroids), the wound healing process, and the initiation of radiotherapy and chemotherapy, which all occur within a few weeks. Accordingly, logistical challenges include the need for rapid testing of biomarkers (which might require shipment of biological samples), generation of the vaccine at a remote location, and delivery of the vaccine back to the hospital setting where the patient will be treated.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-2" data-title="Logistical requirements for autologous immune or immune cell-based vaccination for glioblastoma."><figure><figcaption><b id="Fig2" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 2: Logistical requirements for autologous immune or immune cell-based vaccination for glioblastoma.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/nrneurol.2017.64/figures/2" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnrneurol.2017.64/MediaObjects/41582_2017_Article_BFnrneurol201764_Fig2_HTML.jpg?as=webp"><img aria-describedby="Fig2" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnrneurol.2017.64/MediaObjects/41582_2017_Article_BFnrneurol201764_Fig2_HTML.jpg" alt="figure 2" loading="lazy" width="685" height="272"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-2-desc"><p>Patients undergo apheresis to enable generation of a dendritic cell-based vaccine using peptides derived from tumour-associated antigens. Multiple doses of the vaccine can be produced and used for the patient's treatment. PBMC, peripheral blood mononuclear cell.</p><p> <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nrneurol.2017.64#MOESM104">PowerPoint slide</a> </p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/nrneurol.2017.64/figures/2" data-track-dest="link:Figure2 Full size image" aria-label="Full size image figure 2" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>In this article, we review the experimental evidence supporting the development of vaccine-based immunotherapies for patients with glioma and the clinical experience gathered so far with several such approaches. We also outline current ideas about how to improve the clinical results achieved with glioma vaccines by overcoming specific limitations of current immunotherapies, including efforts to antagonize glioma-associated immunosuppression.</p></div></div></section><section data-title="Data from animal models"><div class="c-article-section" id="Sec2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec2">Data from animal models</h2><div class="c-article-section__content" id="Sec2-content"><p>The use of vaccination to induce immune responses against gliomas has been assessed extensively in rodent models. However, the few available syngeneic mouse glioma models do not fully reflect the biology of human glioma tumours because cell-line-based models do not reproduce the heterogeneity typical of the human disease, and genetically engineered models are, by their nature, a simplification. Furthermore, important differences between mouse and human immune systems must be considered when findings from preclinical models are translated to patients in the clinic<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Oh, T. et al. Immunocompetent murine models for the study of glioblastoma immunotherapy. J. Transl. Med. 12, 107 (2014)." href="/articles/nrneurol.2017.64#ref-CR9" id="ref-link-section-d70610963e696">9</a></sup>. Another important consideration in experimental studies is the timing of vaccination in relation to that of tumour cell inoculation: the longer the gap between initiation of vaccination and tumour cell inoculation, the more potentially relevant are the resulting observations for patients with unresected tumours. Conversely, vaccination soon after tumour cell inoculation (as is typical in rodent studies) might resemble the clinical scenario in patients with recently resected tumours limited to microscopic disease. Despite their limitations, however, preclinical models do provide important information that helps to predict whether glioma vaccines, alone or in combination with other drugs, will have antitumour activity in the clinical setting.</p><p>One of the most frequently used mouse glioma models is based on the GL-261 cell line, which was generated by treatment with the chemical carcinogen methylcholanthrene. These cells are usually implanted stereotactically into the brains of syngeneic C57BL/6 mice, where they produce immunogenic tumours<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Jacobs, V. L., Valdes, P. A., Hickey, W. F. & De Leo, J. A. Current review of in vivo GBM rodent models: emphasis on the CNS-1 tumour model. ASN Neuro 3, e00063 (2011)." href="/articles/nrneurol.2017.64#ref-CR10" id="ref-link-section-d70610963e703">10</a></sup>. A spontaneous glioma that developed in a VM/Dk mouse has been used to generate several syngeneic mouse glioma cell lines<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Serano, R. D., Pegram, C. N. & Bigner, D. D. Tumorigenic cell culture lines from a spontaneous VM/Dk murine astrocytoma (SMA). Acta Neuropathol. 51, 53–64 (1980)." href="/articles/nrneurol.2017.64#ref-CR11" id="ref-link-section-d70610963e707">11</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Sampson, J. H. et al. Characterization of a spontaneous murine astrocytoma and abrogation of its tumorigenicity by cytokine secretion. Neurosurgery 41, 1365–1372 (1997)." href="/articles/nrneurol.2017.64#ref-CR12" id="ref-link-section-d70610963e710">12</a></sup>, which are increasingly used for immunotherapy studies and have the potential advantage over GL-261 that cancer was not chemically induced<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Ahmad, M. et al. How stemlike are sphere cultures from long-term cancer cell lines? Lessons from mouse glioma models. J. Neuropathol. Exp. Neurol. 73, 1062–1077 (2014)." href="/articles/nrneurol.2017.64#ref-CR13" id="ref-link-section-d70610963e714">13</a></sup>. A popular genetic approach uses the RCAS-TVA retroviral gene-transfer system, which can induce syngeneic tumours even in outbred mice<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Fisher, G. H. et al. Development of a flexible and specific gene delivery system for production of murine tumor models. Oncogene 18, 5253–5260 (1999)." href="/articles/nrneurol.2017.64#ref-CR14" id="ref-link-section-d70610963e718">14</a></sup>. A popular transgenic model was created by inactivation of p53 in conjunction with loss of the <i>Nf1</i> gene (encoding neurofibromin)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="Zhu, Y. et al. Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma. Cancer Cell 8, 119–130 (2005)." href="/articles/nrneurol.2017.64#ref-CR15" id="ref-link-section-d70610963e726">15</a></sup>.</p><p>One simple approach to tumour vaccine development is to modify glioma cell lines <i>ex vivo</i> and to use the modified cells as a vaccine against the parent tumour in the mouse brain. For example, the growth of intracerebral SMA-560 gliomas was inhibited by peripheral vaccination using irradiated SMA-560 cells engineered to express MICA (MHC class I polypeptide-related sequence A)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Friese, M. A. et al. MICA/NKG2D-mediated immunogene therapy of experimental gliomas. Cancer Res. 63, 8996–9006 (2003)." href="/articles/nrneurol.2017.64#ref-CR16" id="ref-link-section-d70610963e736">16</a></sup>. MICA is a ligand for NKG2D (NKG2-D type II integral membrane protein), an immunoreceptor expressed on T cells and natural killer (NK) cells that stimulates cellular immune responses<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Ullrich, E., Koch, J., Cerwenka, A. & Steinle, A. New prospects on the NKG2D/NKG2DL system for oncology. Oncoimmunology 2, e26097 (2013)." href="/articles/nrneurol.2017.64#ref-CR17" id="ref-link-section-d70610963e740">17</a></sup>. Other studies have employed cytokine-transduced glioma cells as a vaccine, most using granulocyte–macrophage colony-stimulating factor (GM-CSF)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Herrlinger, U. et al. MIP-1α antagonizes the effect of a GM-CSF-enhanced subcutaneous vaccine in a mouse glioma model. J. Neurooncol. 66, 147–154 (2004)." href="/articles/nrneurol.2017.64#ref-CR18" id="ref-link-section-d70610963e744">18</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Herrlinger, U. et al. Vaccination for experimental gliomas using GM-CSF-transduced glioma cells. Cancer Gene Ther. 4, 345–352 (1997)." href="/articles/nrneurol.2017.64#ref-CR19" id="ref-link-section-d70610963e747">19</a></sup>. The efficacy of vaccines derived from glioma cells might be enhanced by culturing the source cells under hypoxic conditions: vaccination with lysates from GL-261 cells cultured in 5% O<sub>2</sub> caused an increase in cytotoxic T-cell proliferation, tumoricidal function, and trafficking to the tumour site<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Olin, M. R. et al. Superior efficacy of tumor cell vaccines grown in physiologic oxygen. Clin. Cancer Res. 16, 4800–4808 (2010)." href="/articles/nrneurol.2017.64#ref-CR20" id="ref-link-section-d70610963e754">20</a></sup>, although the mechanisms underlying this effect remained obscure.</p><p>Vaccines based on dendritic cells (DCs) have been assessed for approximately two decades in glioma-bearing mice, with variable success<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Heimberger, A. B. et al. Bone marrow-derived dendritic cells pulsed with tumor homogenate induce immunity against syngeneic intracerebral glioma. J. Neuroimmunol. 103, 16–25 (2000)." href="/articles/nrneurol.2017.64#ref-CR21" id="ref-link-section-d70610963e761">21</a></sup>. Effective vaccines have been prepared using DCs pulsed with tumour-specific peptides, tumour lysate, or vectors encoding putative tumour antigens<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Grauer, O. M. et al. Elimination of regulatory T cells is essential for an effective vaccination with tumor lysate-pulsed dendritic cells in a murine glioma model. Int. J. Cancer 122, 1794–1802 (2008)." href="/articles/nrneurol.2017.64#ref-CR22" id="ref-link-section-d70610963e765">22</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Jouanneau, E. et al. Dendritic cells are essential for priming but inefficient for boosting antitumour immune response in an orthotopic murine glioma model. Cancer Immunol. Immunother. 55, 254–267 (2006)." href="/articles/nrneurol.2017.64#ref-CR23" id="ref-link-section-d70610963e768">23</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Yamanaka, R. et al. Marked enhancement of antitumor immune responses in mouse brain tumor models by genetically modified dendritic cells producing Semliki Forest virus-mediated interleukin-12. J. Neurosurg. 97, 611–618 (2002)." href="/articles/nrneurol.2017.64#ref-CR24" id="ref-link-section-d70610963e771">24</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Prins, R. M., Odesa, S. K. & Liau, L. M. Immunotherapeutic targeting of shared melanoma-associated antigens in a murine glioma model. Cancer Res. 63, 8487–8491 (2003)." href="/articles/nrneurol.2017.64#ref-CR25" id="ref-link-section-d70610963e774">25</a></sup>. DC-based vaccination might hold particular promise when the tumour stem cell compartment is used as a source of antigen: in terms of mounting immune responses against orthotopic gliomas, vaccines based on DCs pulsed with a lysate derived from mouse glioma cells were more effective if these glioma cells had stem cell properties<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Pellegatta, S. et al. Neurospheres enriched in cancer stem-like cells are highly effective in eliciting a dendritic cell-mediated immune response against malignant gliomas. Cancer Res. 66, 10247–10252 (2006)." href="/articles/nrneurol.2017.64#ref-CR26" id="ref-link-section-d70610963e778">26</a></sup>.</p><p>Peptide-based vaccines, alone or in combination with therapies aimed at overcoming glioma-associated immunosuppression, have also been investigated in immunocompetent mouse models. For example, an antibody to transforming growth factor-β (TGFβ) augmented the efficacy of vaccination with two peptides, GARC-1<sub>77–85</sub> and EphA2<sub>671–679</sub>, derived from candidate glioma-associated antigens<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Ueda, R. et al. Systemic inhibition of transforming growth factor-β in glioma-bearing mice improves the therapeutic efficacy of glioma-associated antigen peptide vaccines. Clin. Cancer Res. 15, 6551–6559 (2009)." href="/articles/nrneurol.2017.64#ref-CR27" id="ref-link-section-d70610963e790">27</a></sup>.</p><p>Some evidence suggests that vaccines are more effective when given in combination with molecularly targeted therapies. For example, administration of a vaccine derived from DCs pulsed with autologous tumour lysate in combination with antibodies targeting programmed cell death protein 1 (PD1) prolonged the survival of glioma-bearing mice, whereas no such effect was observed with either treatment alone<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Antonios, J. P. et al. PD-1 blockade enhances the vaccination-induced immune response in glioma. JCI Insight 1, e87059 (2016)." href="/articles/nrneurol.2017.64#ref-CR28" id="ref-link-section-d70610963e797">28</a></sup>. Similarly, the efficacy of a vaccine consisting of irradiated GL-261 cells expressing GM-CSF was improved by co-treatment with antibodies targeting cytotoxic T cell antigen 4 (CTLA4)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Agarwalla, P., Barnard, Z., Fecci, P., Dranoff, G. & Curry, W. T. Jr. Sequential immunotherapy by vaccination with GM-CSF-expressing glioma cells and CTLA-4 blockade effectively treats established murine intracranial tumors. J. Immunother. 35, 385–389 (2012)." href="/articles/nrneurol.2017.64#ref-CR29" id="ref-link-section-d70610963e801">29</a></sup>.</p><p>The vast majority of preclinical studies focusing on vaccination in glioblastoma have limitations that impede translation of their findings to the clinic. Specifically, treatment was started very early in relation to the time of tumour cell inoculation, suggesting that vaccine treatment was initiated during immunological priming rather than during the chronic immune homeostasis stage, when treatment is typically initiated in patients with glioblastoma. Moreover, highly immunogenic tumours such as GL-261 were studied, and subcutaneous instead of intracranial tumour cell inoculation was often used, perhaps because researchers erroneously assumed that these two methods would be equally informative<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Huszthy P. C. et al. In vivo models of primary brain tumors: pitfalls and perspectives. Neuro Oncol. 14, 979–993 (2012)." href="/articles/nrneurol.2017.64#ref-CR30" id="ref-link-section-d70610963e808">30</a></sup>. Finally, the age (and thus immune status) of vaccinated mice might not be comparable to that of most patients with glioblastoma. Nonetheless, despite these limitations, mouse models of glioma can lead to a more comprehensive understanding of immune system function, as well as the pitfalls associated with vaccination attempts.</p></div></div></section><section data-title="Data from clinical trials"><div class="c-article-section" id="Sec3-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec3">Data from clinical trials</h2><div class="c-article-section__content" id="Sec3-content"><p>A summary of completed clinical trials of vaccination therapy for gliomas is provided in <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/nrneurol.2017.64#Tab1">Table 1</a>. Ongoing or planned trials are summarized in <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/nrneurol.2017.64#Tab2">Table 2</a>. Current approaches to vaccine-based immunotherapy for glioma exhibit variable degrees of complexity, primarily resulting from selection of the target antigen(s) and the decision whether or not to use autologous, patient-derived immune cells to generate the vaccine (which commonly requires monocyte apheresis and <i>ex vivo</i> maturation into DCs). Selection of the target antigen ranges from approaches targeting a single tumour-specific mutant protein such as isocitrate dehydrogenase (IDH) Arg132His (IDH<sup>R132H</sup>) or epidermal growth factor receptor (EGFR) variant III (EGFRvIII)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Heimberger, A. B. et al. Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors. Clin. Cancer Res. 9, 4247–4254 (2003)." href="/articles/nrneurol.2017.64#ref-CR31" id="ref-link-section-d70610963e831">31</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Schumacher, T. et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512, 324–327 (2014)." href="/articles/nrneurol.2017.64#ref-CR32" id="ref-link-section-d70610963e834">32</a></sup>, to approaches targeting a predefined panel of tumour-associated antigens (such as ICT-107)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Phuphanich, S. et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol. Immunother. 62, 125–135 (2013)." href="/articles/nrneurol.2017.64#ref-CR33" id="ref-link-section-d70610963e839">33</a></sup> or a personalized panel of tumour-associated antigens selected by genome profiling from a limited pool of targets (as used in the GAPVAC trial)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="US National Library of Medicine. ClinicalTrials.gov 
 https://clinicaltrials.gov/ct2/show/NCT02149225
 
 (2016)." href="/articles/nrneurol.2017.64#ref-CR34" id="ref-link-section-d70610963e843">34</a></sup>. Unbiased antigen-selection approaches using undefined tumour-derived peptides (HSPPC-96) or whole-tumour-cell lysates (DCVax) have also been used<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Bloch, O. et al. Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. Neuro Oncol. 16, 274–279 (2014)." href="/articles/nrneurol.2017.64#ref-CR35" id="ref-link-section-d70610963e847">35</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Chiang, C. L., Coukos, G. & Kandalaft, L. E. Whole tumor antigen vaccines: where are we? Vaccines (Basel) 3, 344–372 (2015)." href="/articles/nrneurol.2017.64#ref-CR36" id="ref-link-section-d70610963e850">36</a></sup>.</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-1"><figure><figcaption class="c-article-table__figcaption"><b id="Tab1" data-test="table-caption">Table 1 Completed clinical trials of vaccination therapy for glioblastoma</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/nrneurol.2017.64/tables/1" aria-label="Full size table 1"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-2"><figure><figcaption class="c-article-table__figcaption"><b id="Tab2" data-test="table-caption">Table 2 Ongoing clinical trials of vaccination therapy for glioma</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/nrneurol.2017.64/tables/2" aria-label="Full size table 2"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Vaccines that target defined peptides (as opposed to those targeting uncharacterized proteins or using unbiased antigen selection) are probably less prone to unexpected adverse events, such as induction of tolerance rather than stimulation of immune responses, because the effects of targeting known antigens can be modelled in mice and studied in human cell culture systems, enabling adverse effects to be detected. However, tumour-associated antigens are less likely than tumour-specific antigens to induce immune responses, as high-affinity T cells that respond to tumour-associated antigens are selected against during thymic T-cell development<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Mohme, M., Neidert, M. C., Regli, L., Weller, M. & Martin, R. Immunological challenges for peptide-based immunotherapy in glioblastoma. Cancer Treat. Rev. 40, 248–258 (2014)." href="/articles/nrneurol.2017.64#ref-CR37" id="ref-link-section-d70610963e1612">37</a></sup>. Compared with peptides derived from normal proteins that are overexpressed in gliomas, peptides from altered proteins that are only expressed in tumours, such as EGFRvIII or IDH<sup>R132H</sup>, have the theoretical advantage of tumour specificity and a reduced risk of inducing autoimmunity. Few such antigens have been defined in glioblastoma. Thus, vaccination trials in patients with glioma, and the potential integration of vaccines into standard of care in this setting, might have to overcome obstacles not previously encountered in the clinical management of patients with brain tumours (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nrneurol.2017.64#Fig2">Figs 2</a>,<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nrneurol.2017.64#Fig3">3</a>).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-3" data-title="Putative mode of action for glioblastoma vaccines generated using tumour lysate or peptides."><figure><figcaption><b id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 3: Putative mode of action for glioblastoma vaccines generated using tumour lysate or peptides.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/nrneurol.2017.64/figures/3" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnrneurol.2017.64/MediaObjects/41582_2017_Article_BFnrneurol201764_Fig3_HTML.jpg?as=webp"><img aria-describedby="Fig3" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnrneurol.2017.64/MediaObjects/41582_2017_Article_BFnrneurol201764_Fig3_HTML.jpg" alt="figure 3" loading="lazy" width="685" height="432"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-3-desc"><p>Administration of the vaccine along with an appropriate adjuvant, such as granulocyte–macrophage colony-stimulating factor (GM-CSF), results in antigen-presenting cell (APC) activation and subsequent priming of T helper cells. These processes ultimately induce CD8<sup>+</sup> T cell antitumour immune responses.</p><p> <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nrneurol.2017.64#MOESM105">PowerPoint slide</a> </p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/nrneurol.2017.64/figures/3" data-track-dest="link:Figure3 Full size image" aria-label="Full size image figure 3" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p><b><i>Vaccines targeting EGFRvIII.</i></b> The <i>EGFR</i> gene is amplified in approximately 40% of <i>IDH</i> wild-type glioblastomas<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013)." href="/articles/nrneurol.2017.64#ref-CR38" id="ref-link-section-d70610963e1663">38</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Weller, M. et al. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J. Clin. Oncol. 27, 5743–5750 (2009)." href="/articles/nrneurol.2017.64#ref-CR39" id="ref-link-section-d70610963e1666">39</a></sup>. More than half of such <i>EGFR</i>-amplified tumours exhibit a deletion mutation that results in expression of a truncated protein referred to as EGFRvIII<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Weller, M. et al. Assessment and prognostic significance of the epidermal growth factor receptor vIII mutation in glioblastoma patients treated with concurrent and adjuvant temozolomide radiochemotherapy. Int. J. Cancer 134, 2437–2447 (2014)." href="/articles/nrneurol.2017.64#ref-CR40" id="ref-link-section-d70610963e1673">40</a></sup>. This protein exhibits loss of the ligand-binding domain, resulting in constitutive kinase activity<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Batra, S. K. et al. Epidermal growth factor ligand-independent, unregulated, cell-transforming potential of a naturally occurring human mutant EGFRvIII gene. Cell Growth Differ. 6, 1251–1259 (1995)." href="/articles/nrneurol.2017.64#ref-CR41" id="ref-link-section-d70610963e1678">41</a></sup>. Moreover, the truncated protein exhibits a novel amino acid sequence, which has been identified as potentially immunogenic<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Heimberger, A. B. et al. Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors. Clin. Cancer Res. 9, 4247–4254 (2003)." href="/articles/nrneurol.2017.64#ref-CR31" id="ref-link-section-d70610963e1682">31</a></sup>. A vaccine known as rindopepimut employs this peptide sequence to evoke immune responses, and its efficacy against glioma was explored in three uncontrolled phase II clinical trials, which consistently demonstrated encouraging progression-free and overall survival data<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="Sampson, J. H. et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J. Clin. Oncol. 28, 4722–4729 (2010)." href="/articles/nrneurol.2017.64#ref-CR42" id="ref-link-section-d70610963e1686">42</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 43" title="Sampson, J. H. et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 13, 324–333 (2011)." href="/articles/nrneurol.2017.64#ref-CR43" id="ref-link-section-d70610963e1689">43</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Schuster, J. et al. A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro Oncol. 17, 854–861 (2015)." href="/articles/nrneurol.2017.64#ref-CR44" id="ref-link-section-d70610963e1692">44</a></sup>. Admittedly, the patients vaccinated with rindopepimut in these trials were highly selected, in that the inclusion criteria required gross total tumour resection and an absence of progression at the first scan after completion of chemoradiotherapy<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="Sampson, J. H. et al. Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma. J. Clin. Oncol. 28, 4722–4729 (2010)." href="/articles/nrneurol.2017.64#ref-CR42" id="ref-link-section-d70610963e1696">42</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 43" title="Sampson, J. H. et al. Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma. Neuro Oncol. 13, 324–333 (2011)." href="/articles/nrneurol.2017.64#ref-CR43" id="ref-link-section-d70610963e1699">43</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Schuster, J. et al. A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study. Neuro Oncol. 17, 854–861 (2015)." href="/articles/nrneurol.2017.64#ref-CR44" id="ref-link-section-d70610963e1702">44</a></sup>. The favourable results from these three trials provided the rationale for a pivotal phase III placebo-controlled trial of rindopepimut in patients with newly diagnosed glioblastoma (ACT-IV)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 45" title="Weller, M. et al. ACT IV: an international, double-blind, phase 3 trial of rindopepimut in newly diagnosed, EGFRvIII-expressing glioblastoma. Neuro Oncol. 18, (Suppl. 6), vi17–vi18 (2016)." href="/articles/nrneurol.2017.64#ref-CR45" id="ref-link-section-d70610963e1706">45</a></sup>. Both groups of patients concurrently received standard maintenance temozolomide. However, an interim analysis conducted in early 2016 concluded that the ACT-IV trial should be terminated because the primary end point of improved overall survival was unlikely to be met<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 45" title="Weller, M. et al. ACT IV: an international, double-blind, phase 3 trial of rindopepimut in newly diagnosed, EGFRvIII-expressing glioblastoma. Neuro Oncol. 18, (Suppl. 6), vi17–vi18 (2016)." href="/articles/nrneurol.2017.64#ref-CR45" id="ref-link-section-d70610963e1710">45</a></sup>.</p><p>Despite the negative outcome of this phase III trial, at least three important lessons can be learned from the results of ACT-IV: that the generation of strong humoral immune responses to the vaccine did not translate into a survival benefit; that EGFRvIII expression was lost in approximately half of the patients in each arm of the study, indicating that EGFRvIII expression is not a stable feature of EGFR-amplified glioblastoma; and that a trend towards long-term survival benefit in vaccinated patients was detectable only in those with residual disease<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 45" title="Weller, M. et al. ACT IV: an international, double-blind, phase 3 trial of rindopepimut in newly diagnosed, EGFRvIII-expressing glioblastoma. Neuro Oncol. 18, (Suppl. 6), vi17–vi18 (2016)." href="/articles/nrneurol.2017.64#ref-CR45" id="ref-link-section-d70610963e1717">45</a></sup>. The latter observation contradicts the prevailing hypothesis that minimal residual disease (and, thus, absence of an extensive immunosuppressive micromilieu) is required for immunotherapy to be effective<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 45" title="Weller, M. et al. ACT IV: an international, double-blind, phase 3 trial of rindopepimut in newly diagnosed, EGFRvIII-expressing glioblastoma. Neuro Oncol. 18, (Suppl. 6), vi17–vi18 (2016)." href="/articles/nrneurol.2017.64#ref-CR45" id="ref-link-section-d70610963e1721">45</a></sup>.</p><p>In parallel to ACT-IV, a smaller randomized clinical trial (ReACT) conducted in the USA compared rindopepimut with placebo in patients with recurrent glioblastoma<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 46" title="Reardon, D. A. et al. ReACT: overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma [abstract]. J. Clin. Oncol. 33 (Suppl.), 2009 (2015)." href="/articles/nrneurol.2017.64#ref-CR46" id="ref-link-section-d70610963e1729">46</a></sup>. Both groups of patients also received bevacizumab, the standard of care for this indication in the USA. Data are available in abstract form only, but overall survival seemed to favour the experimental arm (median 11.3 months; 95% CI 9.9–16.2 months) over the control arm (median 9.3 months; 95% CI7.1–11.4 months; HR 0.53, <i>P</i> = 0.0177 in the per-protocol analysis<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 46" title="Reardon, D. A. et al. ReACT: overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma [abstract]. J. Clin. Oncol. 33 (Suppl.), 2009 (2015)." href="/articles/nrneurol.2017.64#ref-CR46" id="ref-link-section-d70610963e1736">46</a></sup>). The primary end point of improved progression-free survival at 6 months was not met, although a beneficial trend in the proportion of patients reaching this end point also favoured the experimental treatment: 28% of patients in the vaccine arm versus 16% of patients in the control arm (<i>P</i> = 0.1163) as ascertained by independent review<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 46" title="Reardon, D. A. et al. ReACT: overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma [abstract]. J. Clin. Oncol. 33 (Suppl.), 2009 (2015)." href="/articles/nrneurol.2017.64#ref-CR46" id="ref-link-section-d70610963e1743">46</a></sup>.</p><p>Why vaccine therapy would show efficacy in patients with recurrent glioblastoma (who have been previously exposed to steroids, radiotherapy and temozolomide chemotherapy) while seeming not to improve outcome in those with newly diagnosed glioblastoma (who should be relatively immunocompetent) remains challenging to understand. One might assume that previous exposure of the tumour cells to genotoxic stress exerted by radiotherapy and alkylating agent chemotherapy would make tumours more immunogenic; also, a transcriptomic profiling study indicated that recurrent tumours are more likely to exhibit a mesenchymal profile, which is characterized by expression of immune and inflammatory genes<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 47" title="Gill, B. J. et al. MRI-localized biopsies reveal subtype-specific differences in molecular and cellular composition at the margins of glioblastoma. Proc. Natl Acad. Sci. USA 111, 12550–12555 (2014)." href="/articles/nrneurol.2017.64#ref-CR47" id="ref-link-section-d70610963e1750">47</a></sup>. Furthermore, the patients in ReACT probably had more-extensive disease than those in ACT-IV, although we must assume, on the basis of data from ACT-IV<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 45" title="Weller, M. et al. ACT IV: an international, double-blind, phase 3 trial of rindopepimut in newly diagnosed, EGFRvIII-expressing glioblastoma. Neuro Oncol. 18, (Suppl. 6), vi17–vi18 (2016)." href="/articles/nrneurol.2017.64#ref-CR45" id="ref-link-section-d70610963e1754">45</a></sup>, that only approximately half of the patients in the ReACT study would have had tumours that were still expressing EGFRvIII by the time of vaccination, as enrolment was based on EGFRvIII expression in the tissue obtained at initial surgery<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 46" title="Reardon, D. A. et al. ReACT: overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma [abstract]. J. Clin. Oncol. 33 (Suppl.), 2009 (2015)." href="/articles/nrneurol.2017.64#ref-CR46" id="ref-link-section-d70610963e1758">46</a></sup>.</p><p>Although experimental data support the combination of vascular endothelial growth factor (VEGF) antagonism and immunotherapy<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 48" title="Johnson, B. F., Clay, T. M., Hobeika, A. C., Lyerly, H. K. & Morse, M. A. Vascular endothelial growth factor and immunosuppression in cancer: current knowledge and potential for new therapy. Exp. Opin. Biol. Ther. 7, 449–460 (2007)." href="/articles/nrneurol.2017.64#ref-CR48" id="ref-link-section-d70610963e1765">48</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 49" title="Voron, T. et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med. 212, 139–148 (2015)." href="/articles/nrneurol.2017.64#ref-CR49" id="ref-link-section-d70610963e1768">49</a></sup>, this combination might not be explored further as clinical development of bevacizumab in glioblastoma has been halted. Two trials reported no improvement in overall survival with bevacizumab therapy in newly diagnosed patients<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Mohme, M., Neidert, M. C., Regli, L., Weller, M. & Martin, R. Immunological challenges for peptide-based immunotherapy in glioblastoma. Cancer Treat. Rev. 40, 248–258 (2014)." href="/articles/nrneurol.2017.64#ref-CR37" id="ref-link-section-d70610963e1772">37</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013)." href="/articles/nrneurol.2017.64#ref-CR38" id="ref-link-section-d70610963e1775">38</a></sup>, and a further trial in patients with recurrent glioblastoma also reported negative results for bevacizumab treatment, albeit in combination with lomustine<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 50" title="Chinot, O. L. et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 709–722 (2014)." href="/articles/nrneurol.2017.64#ref-CR50" id="ref-link-section-d70610963e1779">50</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 51" title="Gilbert, M. R. et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 699–708 (2014)." href="/articles/nrneurol.2017.64#ref-CR51" id="ref-link-section-d70610963e1782">51</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 52" title="Wick, W. et al. EORTC 26101 phase III trial exploring the combination of bevacizumab and lomustine in patients with first progression of a glioblastoma [abstract]. J. Clin. Oncol. 34 (Suppl.), 2001 (2016)." href="/articles/nrneurol.2017.64#ref-CR52" id="ref-link-section-d70610963e1785">52</a></sup>.</p><p>EGFRvIII has also been used as a target for chimeric antigen receptor (CAR)-based T-cell therapy<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 53" title="Johnson, L. A. et al. Rational development and characterization of humanized anti-EGFR variant III chimeric antigen receptor T cells for glioblastoma. Sci. Transl. Med. 7, 275ra22 (2015)." href="/articles/nrneurol.2017.64#ref-CR53" id="ref-link-section-d70610963e1792">53</a></sup>, although as this strategy is not based on vaccination it is outside the scope of the present Review and will not be discussed further. Future trials will show whether CAR T-cell therapy exerts clinically meaningful antitumour activity in patients with glioblastoma.</p><p><b><i>Multipeptide vaccines.</i></b> Multipeptide vaccines have gained increasing interest in the past few years. A vaccine consisting of three peptides derived from glioma-associated antigens has been explored in 26 HLA-A2-positive children with newly diagnosed diffuse intrinsic pontine glioma, anaplastic astrocytoma or glioblastoma<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Pollack, I. F. et al. Antigen-specific immune responses and clinical outcome after vaccination with glioma-associated antigen peptides and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in children with newly diagnosed malignant brainstem and nonbrainstem gliomas. J. Clin. Oncol. 32, 2050–2058 (2014)." href="/articles/nrneurol.2017.64#ref-CR54" id="ref-link-section-d70610963e1801">54</a></sup>. Vaccination was safe and resulted in a measurable immune response<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Pollack, I. F. et al. Antigen-specific immune responses and clinical outcome after vaccination with glioma-associated antigen peptides and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in children with newly diagnosed malignant brainstem and nonbrainstem gliomas. J. Clin. Oncol. 32, 2050–2058 (2014)." href="/articles/nrneurol.2017.64#ref-CR54" id="ref-link-section-d70610963e1805">54</a></sup>, but no conclusions on efficacy can be derived from this uncontrolled study, which pooled several different disease entities. A similar vaccination strategy was also used in a phase I study of patients with WHO grade II glioma<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 55" title="Okada, H. et al. Induction of robust type-I CD8+ T-cell responses in WHO grade 2 low-grade glioma patients receiving peptide-based vaccines in combination with poly-ICLC. Clin. Cancer Res. 21, 286–294 (2015)." href="/articles/nrneurol.2017.64#ref-CR55" id="ref-link-section-d70610963e1809">55</a></sup>. No dose-limiting toxicity was noted, and immune responses against at least three epitopes were observed in most patients<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 55" title="Okada, H. et al. Induction of robust type-I CD8+ T-cell responses in WHO grade 2 low-grade glioma patients receiving peptide-based vaccines in combination with poly-ICLC. Clin. Cancer Res. 21, 286–294 (2015)." href="/articles/nrneurol.2017.64#ref-CR55" id="ref-link-section-d70610963e1813">55</a></sup>.</p><p>Tumour-associated peptides derived from non-mutated proteins are shared to a high degree between different glioblastomas, and their presentation is thought to mainly reflect the presence of deregulated signalling pathways<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 56" title="Dutoit, V. et al. Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy. Brain 135, 1042–1054 (2012)." href="/articles/nrneurol.2017.64#ref-CR56" id="ref-link-section-d70610963e1820">56</a></sup>. Patient-specific selection of tumour-associated peptides might enable the development of an individualized therapeutic cancer vaccine targeting antigens that are not abundantly present in the majority of glioblastomas, but show exceptionally high expression and potential immunogenicity in a given patient's tumour, thereby maximizing the chance of successful induction of relevant immune responses in that individual. IMA950 is one such multipeptide therapeutic vaccine developed for patients with glioblastoma. The IMA950 vaccine includes 11 tumour-associated peptides (nine HLA-A*02 class I peptides, an elongated class I peptide and one class II peptide), as well as the synthetic hepatitis B virus marker peptide IMA-HBV-001. A phase I trial of IMA950 in 45 patients with newly diagnosed glioblastoma receiving maintenance temozolomide has been completed. Treatment-related adverse events were generally mild, but two patients experienced dose-limiting fatigue or anaphylaxis<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 57" title="Rampling, R. et al. A Cancer Research UK first time in human phase I trial of IMA950 (novel multipeptide therapeutic vaccine) in patients with newly diagnosed glioblastoma. Clin. Cancer Res. 22, 4776–4785 (2016)." href="/articles/nrneurol.2017.64#ref-CR57" id="ref-link-section-d70610963e1824">57</a></sup>. Ultimately, 36 of 40 evaluable patients were characterized as single-peptide responders, and 20 patients were characterized as multipeptide responders (according to the vaccine-specific T-cell response criteria defined in the trial protocol). However, progression-free survival was only 74% at 6 months and 31% at 9 months, and median overall survival was 15.3 months<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 57" title="Rampling, R. et al. A Cancer Research UK first time in human phase I trial of IMA950 (novel multipeptide therapeutic vaccine) in patients with newly diagnosed glioblastoma. Clin. Cancer Res. 22, 4776–4785 (2016)." href="/articles/nrneurol.2017.64#ref-CR57" id="ref-link-section-d70610963e1828">57</a></sup>.</p><p>Taking the concept of personalized vaccines to the next level of individualization, the Glioma Actively Personalized Vaccines Consortium (GAPVAC) initiated a phase I trial of vaccines based on individualized selection of both tumour-associated peptides and tumour-specific peptides<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="US National Library of Medicine. ClinicalTrials.gov 
 https://clinicaltrials.gov/ct2/show/NCT02149225
 
 (2016)." href="/articles/nrneurol.2017.64#ref-CR34" id="ref-link-section-d70610963e1836">34</a></sup>. The term actively personalized vaccine (APVAC) had been previously coined by the Regulatory Research Group of the Association of Cancer Immunotherapy<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 58" title="Britten, C. M. et al. The regulatory landscape for actively personalized cancer immunotherapies. Nat. Biotechnol. 31, 880–882 (2013)." href="/articles/nrneurol.2017.64#ref-CR58" id="ref-link-section-d70610963e1840">58</a></sup>. In the GAPVAC-101 trial, both APVACs were integrated into standard care (surgery and chemoradiotherapy followed by maintenance temozolomide) in newly diagnosed patients with glioblastoma<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="US National Library of Medicine. ClinicalTrials.gov 
 https://clinicaltrials.gov/ct2/show/NCT02149225
 
 (2016)." href="/articles/nrneurol.2017.64#ref-CR34" id="ref-link-section-d70610963e1844">34</a></sup>. APVAC 1 vaccines contained 5–10 peptides selected from a library of proteins obtained by expression profiling of the patient's tumour; the peptides most strongly associated with the tumour were selected for each patient to maximize the number of effective antitumour immune responses. APVAC 2 vaccines contained 1–2 custom-made synthetic mutated peptides. Next-generation sequencing and mass spectrometry were employed to compare the tumour and patient genomes and identify suitable mutated peptides for this purpose.</p><p>Another novel multipeptide vaccination strategy utilizes neoepitopes derived from mutant peptides expressed on an individual patient's tumour. A feasibility trial evaluating the administration of up to 20 neoepitopes per patient has been initiated as an individualized tumour vaccine strategy in patients with newly diagnosed glioblastoma<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 59" title="US National Library of Medicine. ClinicalTrials.gov 
 https://clinicaltrials.gov/ct2/show/NCT02287428
 
 (2016)." href="/articles/nrneurol.2017.64#ref-CR59" id="ref-link-section-d70610963e1851">59</a></sup>. Results of these approaches are eagerly awaited.</p><p><b><i>Dendritic-cell-based vaccines.</i></b> DCs have been used for many years to generate vaccines for use in both paediatric and adult patients with glioma. Most clinical reports describe single-centre experiences, however, and many open questions remain with regard to the precise conduct of the treatment<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 60" title="Ardon, H. et al. Adjuvant dendritic cell-based tumour vaccination for children with malignant brain tumours. Pediatr. Blood Cancer 54, 519–525 (2010)." href="/articles/nrneurol.2017.64#ref-CR60" id="ref-link-section-d70610963e1860">60</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 61" title="Ardon, H. et al. Integration of autologous dendritic cell-based immunotherapy in the standard of care treatment for patients with newly diagnosed glioblastoma: results of the HGG-2006 phase I/II trial. Cancer Immunol. Immunother. 61, 2033–2044 (2012)." href="/articles/nrneurol.2017.64#ref-CR61" id="ref-link-section-d70610963e1863">61</a></sup>.</p><p>In an early phase I trial in adults with glioblastoma, autologous DCs were pulsed with acid-eluted autologous tumour peptides to yield the vaccine<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 62" title="Liau, L. M. et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin. Cancer Res. 11, 5515–5525 (2005)." href="/articles/nrneurol.2017.64#ref-CR62" id="ref-link-section-d70610963e1870">62</a></sup>. The researchers concluded that the absence of bulky, progressive disease and low expression of TGFβ2 defined a subgroup of patients who might be most suitable for further studies of vaccine efficacy<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 62" title="Liau, L. M. et al. Dendritic cell vaccination in glioblastoma patients induces systemic and intracranial T-cell responses modulated by the local central nervous system tumor microenvironment. Clin. Cancer Res. 11, 5515–5525 (2005)." href="/articles/nrneurol.2017.64#ref-CR62" id="ref-link-section-d70610963e1874">62</a></sup>. An ensuing phase I study in 23 such patients combined this vaccination approach with Toll-like receptor (TLR) agonist treatment<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 63" title="Prins, R. M. et al. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin. Cancer Res. 17, 1603–1615 (2011)." href="/articles/nrneurol.2017.64#ref-CR63" id="ref-link-section-d70610963e1878">63</a></sup>. The results led to the hypothesis that glioblastomas with a mesenchymal gene-expression profile exhibit increased immune cell infiltration associated with increased immunogenicity, and are, therefore, more amenable to immunotherapy than are tumours with other profiles<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 63" title="Prins, R. M. et al. Gene expression profile correlates with T-cell infiltration and relative survival in glioblastoma patients vaccinated with dendritic cell immunotherapy. Clin. Cancer Res. 17, 1603–1615 (2011)." href="/articles/nrneurol.2017.64#ref-CR63" id="ref-link-section-d70610963e1882">63</a></sup>. DCVax is an ongoing phase III trial of a DC vaccine generated with autologous tumour lysate, and was based on the experience summarized above, but is not recruiting patients at present<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 64" title="US National Library of Medicine. ClinicalTrials.gov 
 https://clinicaltrials.gov/ct2/show/NCT00045968
 
 (2016)." href="/articles/nrneurol.2017.64#ref-CR64" id="ref-link-section-d70610963e1886">64</a></sup>.</p><p>Another phase I–II trial assessed the activity of a DC-based multipeptide vaccine derived from glioma-associated antigens in 22 patients: 13 with glioblastoma, five with anaplastic astrocytoma, three with anaplastic oligodendroglioma, and one with anaplastic oligoastrocytoma<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 65" title="Okada, H. et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with α-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J. Clin. Oncol. 29, 330–336 (2011)." href="/articles/nrneurol.2017.64#ref-CR65" id="ref-link-section-d70610963e1893">65</a></sup>. This trial yielded findings suggestive of clinical efficacy. In total, nine vaccinated patients (41%) — four with glioblastoma and five with anaplastic glioma — remained progression-free for ≥12 months<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 65" title="Okada, H. et al. Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with α-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in patients with recurrent malignant glioma. J. Clin. Oncol. 29, 330–336 (2011)." href="/articles/nrneurol.2017.64#ref-CR65" id="ref-link-section-d70610963e1897">65</a></sup>. The clinically most advanced DC-based vaccine to date is ICT-107, which is generated by exposing autologous patient-derived DCs to peptides derived from six proteins predicted to be abundant in glioblastoma and thought to be linked to the glioma stem cell signature<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Phuphanich, S. et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol. Immunother. 62, 125–135 (2013)." href="/articles/nrneurol.2017.64#ref-CR33" id="ref-link-section-d70610963e1901">33</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 66" title="Wen, P. et al. A randomized double blind placebo-controlled phase 2 trial of dendritic cell (DC) vaccine ICT-107 following standard treatment in newly diagnosed patients with GBM. Neuro Oncol. 16 (Suppl. 5), v22 (2014)." href="/articles/nrneurol.2017.64#ref-CR66" id="ref-link-section-d70610963e1904">66</a></sup>. These six proteins are glycoprotein 100 (gp100), melanoma-associated antigen 1 (MAGE1), interferon-inducible protein AIM2 (also known as absent in melanoma 2), tyrosine kinase-type cell surface receptor HER2 (also known as proto-oncogene Neu or receptor tyrosine-protein kinase erbB2), IL-13Rα2 (IL-13 receptor subunit α2), and tyrosinase related protein-2 (TRP2). The MAGE1 and AIM2 peptides were predicted to be HLA-A1-associated whereas the other four epitopes were predicted to be HLA-A2-associated<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 66" title="Wen, P. et al. A randomized double blind placebo-controlled phase 2 trial of dendritic cell (DC) vaccine ICT-107 following standard treatment in newly diagnosed patients with GBM. Neuro Oncol. 16 (Suppl. 5), v22 (2014)." href="/articles/nrneurol.2017.64#ref-CR66" id="ref-link-section-d70610963e1908">66</a></sup>. The safety of the ICT-107 vaccine was confirmed in a phase I trial that enrolled 21 patients (17 with newly diagnosed glioblastoma, three with recurrent glioblastoma and one with brainstem glioma)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Phuphanich, S. et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol. Immunother. 62, 125–135 (2013)." href="/articles/nrneurol.2017.64#ref-CR33" id="ref-link-section-d70610963e1912">33</a></sup>. Median progression-free survival in the newly diagnosed patients was 16.9 months, and median overall survival was 38.4 months, data which the researchers interpreted as encouraging. An increased duration of both overall survival and progression-free survival correlated with gene expression related to four of the six target proteins in the newly diagnosed glioblastoma cohort<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Phuphanich, S. et al. Phase I trial of a multi-epitope-pulsed dendritic cell vaccine for patients with newly diagnosed glioblastoma. Cancer Immunol. Immunother. 62, 125–135 (2013)." href="/articles/nrneurol.2017.64#ref-CR33" id="ref-link-section-d70610963e1917">33</a></sup>.</p><p>The ensuing randomized phase II trial of ICT-107 did not meet the primary end point of improved overall survival<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 66" title="Wen, P. et al. A randomized double blind placebo-controlled phase 2 trial of dendritic cell (DC) vaccine ICT-107 following standard treatment in newly diagnosed patients with GBM. Neuro Oncol. 16 (Suppl. 5), v22 (2014)." href="/articles/nrneurol.2017.64#ref-CR66" id="ref-link-section-d70610963e1924">66</a></sup>. However, <i>post hoc</i> analyses revealed that a potential benefit was probably restricted to the subgroup of HLA-A2-positive individuals, who accounted for 77 of the 124 (62%) patients who underwent randomization. Moreover, the lack of an MRI scan to rule out progression at the time of randomization (that is, after completion of concomitant temozolomide and radiotherapy) might have accounted for the inclusion of patients with early progression in the group without promoter methylation of <i>MGMT</i> (methylated-DNA — protein-cysteine methyltransferase), which could have contributed to the failure to reach the primary end point<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 66" title="Wen, P. et al. A randomized double blind placebo-controlled phase 2 trial of dendritic cell (DC) vaccine ICT-107 following standard treatment in newly diagnosed patients with GBM. Neuro Oncol. 16 (Suppl. 5), v22 (2014)." href="/articles/nrneurol.2017.64#ref-CR66" id="ref-link-section-d70610963e1934">66</a></sup>. On the basis of this phase II experience, a pivotal phase III trial of ICT-107 has been initiated, which mandates confirmation of the absence of progression after completion of chemoradiotherapy and limits enrolment to HLA-A2-positive patients<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 67" title="US National Library of Medicine. ClinicalTrials.gov 
 https://clinicaltrials.gov/ct2/show/NCT02546102
 
 (2017)." href="/articles/nrneurol.2017.64#ref-CR67" id="ref-link-section-d70610963e1938">67</a></sup>.</p><p><b><i>IDH</i></b><sup><b><i>R132H</i></b></sup><b><i>-specific vaccines.</i></b> Evidence for the therapeutic efficacy of IDH<sup>R132H</sup>-specific vaccines stems from preclinical studies in a humanized mouse sarcoma model<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Schumacher, T. et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512, 324–327 (2014)." href="/articles/nrneurol.2017.64#ref-CR32" id="ref-link-section-d70610963e1955">32</a></sup> and an orthotopic syngeneic mouse glioma model<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 68" title="Pellegatta, S. et al. Effective immuno-targeting of the IDH1 mutation R132H in a murine model of intracranial glioma. Acta Neuropathol. Commun. 3, 4 (2015)." href="/articles/nrneurol.2017.64#ref-CR68" id="ref-link-section-d70610963e1959">68</a></sup>. <i>IDH1</i> is mutated in more than 70% of diffuse and anaplastic gliomas, but only approximately 5% of glioblastomas<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 69" title="Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009)." href="/articles/nrneurol.2017.64#ref-CR69" id="ref-link-section-d70610963e1967">69</a></sup>. The vast majority of <i>IDH1</i> mutations result in a protein with an arginine to histidine amino acid substitution at position 132 (IDH<sup>R132H</sup>)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 70" title="Hartmann, C. et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol. 118, 469–474 (2009)." href="/articles/nrneurol.2017.64#ref-CR70" id="ref-link-section-d70610963e1976">70</a></sup>. In addition to the metabolic and epigenetic consequences of this mutation with regard to gliomagenesis and tumour behaviour<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 71" title="Waitkus, M. S., Diplas, B. H. & Yan, H. Isocitrate dehydrogenase mutations in gliomas. Neuro Oncol. 18, 16–26 (2016)." href="/articles/nrneurol.2017.64#ref-CR71" id="ref-link-section-d70610963e1980">71</a></sup>, IDH<sup>R132H</sup> harbours a neoepitope that, similarly to many other mutated antigens<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 72" title="Platten, M. & Offringa, R. Cancer immunotherapy: exploiting neoepitopes. Cell Res. 25, 887–888 (2015)." href="/articles/nrneurol.2017.64#ref-CR72" id="ref-link-section-d70610963e1987">72</a></sup>, is presented by professional antigen-presenting cells or MHC class II-expressing glioma cells<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 73" title="Bunse, L. et al. Proximity ligation assay evaluates IDH1 R132H presentation in gliomas. J. Clin. Invest. 125, 593–606 (2015)." href="/articles/nrneurol.2017.64#ref-CR73" id="ref-link-section-d70610963e1991">73</a></sup>, thereby stimulating mutation-specific CD4<sup>+</sup> T-cell responses<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 74" title="Melief, C. J. Mutation-specific T cells for immunotherapy of gliomas. N. Engl. J. Med. 372, 1956–1958 (2015)." href="/articles/nrneurol.2017.64#ref-CR74" id="ref-link-section-d70610963e1997">74</a></sup>. Indeed, spontaneous T-cell and antibody responses to IDH<sup>R132H</sup> are observed in a fraction of patients with glioma<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Schumacher, T. et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512, 324–327 (2014)." href="/articles/nrneurol.2017.64#ref-CR32" id="ref-link-section-d70610963e2003">32</a></sup>. The IDH<sup>R132H</sup> neoepitope also seems to be capable of presentation by multiple MHC class II allelotypes.</p><p>From an immunological perspective, the IDH<sup>R132H</sup> mutation represents an interesting target for immunotherapy as it is not only tumour-specific but also expressed in all tumour cells and, thus, represents a clonal neoantigen with high uniformity and penetrance. In human immune responses to IDH<sup>R132H</sup>, only mutation-specific CD4<sup>+</sup> T cells have been observed<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Schumacher, T. et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512, 324–327 (2014)." href="/articles/nrneurol.2017.64#ref-CR32" id="ref-link-section-d70610963e2019">32</a></sup>. In the absence of mutation-specific CD8<sup>+</sup> T effector cells, the cellular mechanisms of the efferent arm of the therapeutic response remain unclear, but the preclinical data suggest that B cells are required<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 75" title="Schumacher, T., Bunse, L., Wick, W. & Platten, M. Mutant IDH1: an immunotherapeutic target in tumors. Oncoimmunology 3, e974392 (2014)." href="/articles/nrneurol.2017.64#ref-CR75" id="ref-link-section-d70610963e2026">75</a></sup>.</p><p>The ongoing NOA-16 trial<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 76" title="US National Library of Medicine. ClinicalTrials.gov 
 https://clinicaltrials.gov/ct2/show/NCT02454634
 
 (2016)." href="/articles/nrneurol.2017.64#ref-CR76" id="ref-link-section-d70610963e2033">76</a></sup> is a phase I safety, tolerability and immunogenicity multicentre study evaluating a 20-mer IDH<sup>R132H</sup> peptide in patients with treatment-naive WHO grade III–IV <i>IDH1</i>-mutated gliomas. Patient enrolment is not confined to a specific MHC class II haplotype, but the trial population is enriched for an unfavourable prognosis by restricting enrolment to patients whose tumours have an astrocytic molecular phenotype. Eight vaccines are integrated in the primary therapy, which in most patients comprises radiochemotherapy combined with temozolomide. The trial is accompanied by a translational research programme that aims to identify key biomarkers for predicting and monitoring response to the vaccine<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 76" title="US National Library of Medicine. ClinicalTrials.gov 
 https://clinicaltrials.gov/ct2/show/NCT02454634
 
 (2016)." href="/articles/nrneurol.2017.64#ref-CR76" id="ref-link-section-d70610963e2042">76</a></sup>. This important initiative will characterize the immunological mechanism of the (primarily T-helper-cell-driven) antitumour immune response, and promote the development of rational combination therapies. However, concerns regarding efforts to target mutant IDH<sup>R132H</sup> have been expressed, as this mutated protein negatively regulates the growth of gliomas when exogenously transduced<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 77" title="Li, S. et al. Overexpression of isocitrate dehydrogenase mutant proteins renders glioma cells more sensitive to radiation. Neuro Oncol. 15, 57–68 (2013)." href="/articles/nrneurol.2017.64#ref-CR77" id="ref-link-section-d70610963e2049">77</a></sup>. However, given that a vaccine would target cells expressing IDH<sup>R132H</sup> rather than the mutant protein itself, these concerns are unlikely to reflect the scenario of the therapeutic approach.</p><p><b><i>HSPPC-96.</i></b> Heat-shock proteins (HSPs) are involved in cellular responses to stressors such as heat, from which this protein family derived its name. Notably, HSP-96 can bind tumour-associated antigens, and HSP-96 — peptide complex (HSPPC-96) can be taken up by antigen-presenting cells, potentially triggering specific antitumour responses<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 78" title="Suto, R. & Srivastava, P. K. A mechanism for the specific immunogenicity of heat shock protein-chaperoned peptides. Science 269, 1585–1588 (1995)." href="/articles/nrneurol.2017.64#ref-CR78" id="ref-link-section-d70610963e2060">78</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 79" title="Tamura, Y., Peng, P., Liu, K., Daou, M. & Srivastava, P. K. Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations. Science 278, 117–120 (1997)." href="/articles/nrneurol.2017.64#ref-CR79" id="ref-link-section-d70610963e2063">79</a></sup>. HSPPC-96 has, therefore, been used to generate vaccines that aim to boost antitumour immune responses<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 80" title="Ampie, L. et al. Heat shock protein vaccines against glioblastoma: from bench to bedside. J. Neurooncol. 123, 441–448 (2015)." href="/articles/nrneurol.2017.64#ref-CR80" id="ref-link-section-d70610963e2067">80</a></sup>.</p><p>HSPPC-96 vaccination of patients with recurrent glioblastoma resulted in specific immune responses in the blood as well at the tumour site<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 81" title="Crane, C. A. et al. Individual patient-specific immunity against high-grade glioma after vaccination with autologous tumor derived peptides bound to the 96 kD chaperone protein. Clin. Cancer Res. 19, 205–214 (2013)." href="/articles/nrneurol.2017.64#ref-CR81" id="ref-link-section-d70610963e2074">81</a></sup>. A subsequent phase II trial enrolled 41 patients with recurrent glioblastoma who had undergone complete resection of the tumour. Survival was 90.2% at 6 months and 29.3% at 12 months<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Bloch, O. et al. Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. Neuro Oncol. 16, 274–279 (2014)." href="/articles/nrneurol.2017.64#ref-CR35" id="ref-link-section-d70610963e2078">35</a></sup>. In the absence of a control group in this trial, however, no statement on vaccine efficacy can be made<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Bloch, O. et al. Heat-shock protein peptide complex-96 vaccination for recurrent glioblastoma: a phase II, single-arm trial. Neuro Oncol. 16, 274–279 (2014)." href="/articles/nrneurol.2017.64#ref-CR35" id="ref-link-section-d70610963e2082">35</a></sup>. Current limitations on the use of HSPPC-96-based vaccines include the necessity of prior tumour resection, as 7 g of tumour tissue is needed to prepare at least four 25 μg doses of vaccine. A randomized phase II trial of HSPPC-96 vaccination in patients with newly diagnosed glioblastoma is ongoing<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 82" title="US National Library of Medicine. ClinicalTrials.gov 
 https://clinicaltrials.gov/ct2/show/NCT03018288
 
 (2017)." href="/articles/nrneurol.2017.64#ref-CR82" id="ref-link-section-d70610963e2086">82</a></sup> (<a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/nrneurol.2017.64#Tab2">Table 2</a>).</p><p><b><i>Cytomegalovirus proteins.</i></b> Several groups have demonstrated that human cytomegalovirus (CMV) proteins are expressed in >90% of glioblastomas<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 83" title="Mitchell, D. A. et al. Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol. 10, 10–18 (2008)." href="/articles/nrneurol.2017.64#ref-CR83" id="ref-link-section-d70610963e2098">83</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 84" title="Cobbs, C. S. et al. Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res. 62, 3347–3350 (2002)." href="/articles/nrneurol.2017.64#ref-CR84" id="ref-link-section-d70610963e2101">84</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 85" title="Prins, R. M., Cloughesy, T. F. & Liau, L. M. Cytomegalovirus immunity after vaccination with autologous glioblastoma lysate. N. Engl. J. Med. 359, 539–541 (2008)." href="/articles/nrneurol.2017.64#ref-CR85" id="ref-link-section-d70610963e2104">85</a></sup>, although other researchers have failed to detect human CMV protein or DNA in glioblastoma samples<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 86" title="Baumgarten, P. et al. Human cytomegalovirus infection in tumor cells of the nervous system is not detectable with standardized pathologico-virological diagnostics. Neuro Oncol. 16, 1469–1477 (2014)." href="/articles/nrneurol.2017.64#ref-CR86" id="ref-link-section-d70610963e2108">86</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 87" title="Tang, K. W., Hellstrand, K. & Larsson, E. Absence of cytomegalovirus in high-coverage DNA sequencing of human glioblastoma multiforme. Int. J. Cancer 136, 977–981 (2015)." href="/articles/nrneurol.2017.64#ref-CR87" id="ref-link-section-d70610963e2111">87</a></sup>. Expression of CMV protein has not been detected in normal brain tissue surrounding virus-positive glioblastomas<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 83" title="Mitchell, D. A. et al. Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol. 10, 10–18 (2008)." href="/articles/nrneurol.2017.64#ref-CR83" id="ref-link-section-d70610963e2115">83</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 84" title="Cobbs, C. S. et al. Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res. 62, 3347–3350 (2002)." href="/articles/nrneurol.2017.64#ref-CR84" id="ref-link-section-d70610963e2118">84</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 88" title="Dziurzynski, K. et al. Consensus on the role of human cytomegalovirus in glioblastoma. Neuro Oncol. 14, 246–255 (2012)." href="/articles/nrneurol.2017.64#ref-CR88" id="ref-link-section-d70610963e2121">88</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 89" title="Ranganathan, P., Clark, P. A., Kuo, J. S., Salamat, M. S. & Kalejta, R. F. Significant association of multiple human cytomegalovirus genomic loci with glioblastoma multiforme samples. J. Virol. 86, 854–864 (2012)." href="/articles/nrneurol.2017.64#ref-CR89" id="ref-link-section-d70610963e2124">89</a></sup>, suggesting that viral antigens could be subverted as tumour-specific targets. Subclinical reactivation of latent CMV infection is frequent in critically ill and immunocompromised patients<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 90" title="Limaye, A. P. et al. Cytomegalovirus reactivation in critically ill immunocompetent patients. JAMA 300, 413–422 (2008)." href="/articles/nrneurol.2017.64#ref-CR90" id="ref-link-section-d70610963e2128">90</a></sup>, and DCs pulsed with CMV antigens are potent inducers of virus-specific immune responses<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 91" title="Kleihauer, A. et al. Ex vivo generation of human cytomegalovirus-specific cytotoxic T cells by peptide-pulsed dendritic cells. Br. J. Haematol. 113, 231–239 (2001)." href="/articles/nrneurol.2017.64#ref-CR91" id="ref-link-section-d70610963e2132">91</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 92" title="Cho, H. I., Han, H., Kim, C. C. & Kim, T. G. Generation of cytotoxic T lymphocytes specific for human cytomegalovirus using dendritic cells in vitro. J. Immunother. 24, 242–249 (2001)." href="/articles/nrneurol.2017.64#ref-CR92" id="ref-link-section-d70610963e2135">92</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 93" title="Raftery, M. J., Schwab, M., Diesner, S., Egerer, G. & Schonrich, G. Dendritic cells cross-presenting viral antigens derived from autologous cells as a sensitive tool for visualization of human cytomegalovirus-reactive CD8+ T cells. Transplantation 73, 998–1002 (2002)." href="/articles/nrneurol.2017.64#ref-CR93" id="ref-link-section-d70610963e2138">93</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 94" title="Peggs, K. S. & Mackinnon, S. Clinical trials with CMV-specific T cells. Cytotherapy 4, 21–28 (2002)." href="/articles/nrneurol.2017.64#ref-CR94" id="ref-link-section-d70610963e2141">94</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 95" title="Szmania, S. et al. Isolation and expansion of cytomegalovirus-specific cytotoxic T lymphocytes to clinical scale from a single blood draw using dendritic cells and HLA-tetramers. Blood 98, 505–512 (2001)." href="/articles/nrneurol.2017.64#ref-CR95" id="ref-link-section-d70610963e2144">95</a></sup>.</p><p>A study published in 2014 demonstrated that CMV-specific T-cell immune responses can recognize and effectively kill autologous glioblastoma cells expressing the immunodominant pp65 viral antigen at endogenous levels<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 96" title="Nair, S. K. et al. Recognition and killing of autologous, primary glioblastoma tumor cells by human cytomegalovirus pp65-specific cytotoxic T cells. Clin. Cancer Res. 20, 2684–2694 (2014)." href="/articles/nrneurol.2017.64#ref-CR96" id="ref-link-section-d70610963e2152">96</a></sup>, supporting the development of CMV-directed immunotherapy. Moreover, CMV-reactive T cells might recognize glioblastoma cells independently of CMV antigen expression<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 97" title="Knight, A. et al. CMV-independent lysis of glioblastoma by ex vivo expanded/activated Vδ1+ γδ T cells. PLoS ONE 8, e68729 (2013)." href="/articles/nrneurol.2017.64#ref-CR97" id="ref-link-section-d70610963e2156">97</a></sup>. In a small randomized pilot trial, patients who received CMV pp65-specific DCs in combination with vaccine-site preconditioning using tetanus–diphtheria toxoid showed better than predicted progression-free survival (median 10.8 months) and overall survival (median 18.5 months) from diagnosis<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 98" title="Mitchell, D. A. et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients. Nature 519, 366–369 (2015)." href="/articles/nrneurol.2017.64#ref-CR98" id="ref-link-section-d70610963e2160">98</a></sup>.</p></div></div></section><section data-title="Boosting immune responses to glioma"><div class="c-article-section" id="Sec4-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec4">Boosting immune responses to glioma</h2><div class="c-article-section__content" id="Sec4-content"><p>As summarized in <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nrneurol.2017.64#Fig1">Figure 1</a>, multiple mechanisms (including cell-surface-based and paracrine pathways) mediate glioma-associated immunosuppression<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 49" title="Voron, T. et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J. Exp. Med. 212, 139–148 (2015)." href="/articles/nrneurol.2017.64#ref-CR49" id="ref-link-section-d70610963e2175">49</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 99" title="Roth, P. et al. GDF-15 contributes to proliferation and immune escape of malignant gliomas. Clin. Cancer Res. 16, 3851–3859 (2010)." href="/articles/nrneurol.2017.64#ref-CR99" id="ref-link-section-d70610963e2178">99</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 100" title="Wu, A. et al. Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro Oncol. 12, 1113–1125 (2010)." href="/articles/nrneurol.2017.64#ref-CR100" id="ref-link-section-d70610963e2181">100</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 101" title="Hishii, M. et al. Human glioma-derived interleukin-10 inhibits antitumor immune responses in vitro. Neurosurgery 37, 1160–1166 (1995)." href="/articles/nrneurol.2017.64#ref-CR101" id="ref-link-section-d70610963e2184">101</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 102" title="Wolpert, F. et al. HLA-E contributes to an immune-inhibitory phenotype of glioblastoma stem-like cells. J. Neuroimmunol. 250, 27–34 (2012)." href="/articles/nrneurol.2017.64#ref-CR102" id="ref-link-section-d70610963e2187">102</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 103" title="Lemke, D. et al. Costimulatory protein 4IgB7H3 drives the malignant phenotype of glioblastoma by mediating immune escape and invasiveness. Clin. Cancer Res. 18, 105–117 (2012)." href="/articles/nrneurol.2017.64#ref-CR103" id="ref-link-section-d70610963e2190">103</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 104" title="Codo, P. et al. MicroRNA-mediated down-regulation of NKG2D ligands contributes to glioma immune escape. Oncotarget 5, 7651–7662 (2014)." href="/articles/nrneurol.2017.64#ref-CR104" id="ref-link-section-d70610963e2194">104</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 105" title="Lauro, G. M., Di Lorenzo, N., Grossi, M., Maleci, A. & Guidetti, B. Prostaglandin E2 as an immunomodulating factor released in vitro by human glioma cells. Acta Neuropathol. 69, 278–282 (1986)." href="/articles/nrneurol.2017.64#ref-CR105" id="ref-link-section-d70610963e2197">105</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 106" title="Ichinose, M., Masuoka, J., Shiraishi, T., Mineta, T. & Tabuchi, K. Fas ligand expression and depletion of T-cell infiltration in astrocytic tumors. Brain Tumor Pathol. 18, 37–42 (2001)." href="/articles/nrneurol.2017.64#ref-CR106" id="ref-link-section-d70610963e2200">106</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 107" title="Roth, P. et al. Malignant glioma cells counteract antitumor immune responses through expression of lectin-like transcript-1. Cancer Res. 67, 3540–3544 (2007)." href="/articles/nrneurol.2017.64#ref-CR107" id="ref-link-section-d70610963e2203">107</a></sup>, which is likely to limit the efficacy of active immunotherapy in the absence of effective countermeasures. Accordingly, this situation offers a strong rationale for combining specific immunological targeting via a glioma-specific vaccine with necessarily nonspecific approaches to reduce local and systemic immunosuppression, as described below.</p><p><b><i>Immune checkpoint modulators.</i></b> The most straightforward approach to increase general immune responsiveness is administration of immune checkpoint modulators. Immune checkpoint inhibitors are therapeutic monoclonal antibodies that intercept receptor–ligand interactions involved in regulating immune cell activity. These drugs might, therefore, relieve glioma-associated immunosuppression and facilitate tumour cell destruction by immune cells<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 108" title="Preusser, M., Lim, M., Hafler, D. A., Reardon, D. A. & Sampson, J. H. Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat. Rev. Neurol. 11, 504–514 (2015)." href="/articles/nrneurol.2017.64#ref-CR108" id="ref-link-section-d70610963e2212">108</a></sup> (<a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/nrneurol.2017.64#Fig4">Fig. 4</a>). Immune checkpoint inhibitors such as ipilimumab (which targets CTLA4), nivolumab and pembrolizumab (which target PD1), and atezolizumab and durvalumab (which target PDL1) have shown remarkable and sometimes lasting activity against several cancer types, including melanoma, lung cancer, renal cell cancer, bladder cancer, head and neck cancer, and Hodgkin lymphoma<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 109" title="Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010)." href="/articles/nrneurol.2017.64#ref-CR109" id="ref-link-section-d70610963e2219">109</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 110" title="Robert, C. et al. Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 372, 2521–2532 (2015)." href="/articles/nrneurol.2017.64#ref-CR110" id="ref-link-section-d70610963e2222">110</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 111" title="Rizvi, N. A. et al. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Lancet Oncol. 16, 257–265 (2015)." href="/articles/nrneurol.2017.64#ref-CR111" id="ref-link-section-d70610963e2225">111</a></sup>.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-4" data-title="Facilitating effective vaccination by neutralizing glioma-associated immunosuppression."><figure><figcaption><b id="Fig4" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 4: Facilitating effective vaccination by neutralizing glioma-associated immunosuppression.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/nrneurol.2017.64/figures/4" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnrneurol.2017.64/MediaObjects/41582_2017_Article_BFnrneurol201764_Fig4_HTML.jpg?as=webp"><img aria-describedby="Fig4" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fnrneurol.2017.64/MediaObjects/41582_2017_Article_BFnrneurol201764_Fig4_HTML.jpg" alt="figure 4" loading="lazy" width="685" height="552"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-4-desc"><p>Immune checkpoint inhibition using therapeutic monoclonal antibodies, such as those directed against PD1 (programmed cell death protein 1) or PDL1 (programmed cell death 1 ligand 1), might counteract glioma-associated immunosuppression in the tumour microenvironment or peripheral immune sites such as regional lymph nodes. Relief of tumour-associated immunosuppression could boost the activity of glioma-specific cytotoxic T lymphocytes (CTL) generated by vaccination.</p><p> <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/nrneurol.2017.64#MOESM106">PowerPoint slide</a> </p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/nrneurol.2017.64/figures/4" data-track-dest="link:Figure4 Full size image" aria-label="Full size image figure 4" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>High expression levels and immunosuppressive activity of the PD1–PDL1 axis have been documented in human glioblastoma<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 112" title="Berghoff, A. S. et al. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro Oncol. 17, 1064–1075 (2015)." href="/articles/nrneurol.2017.64#ref-CR112" id="ref-link-section-d70610963e2257">112</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 113" title="Nduom, E. K. et al. PD-L1 expression and prognostic impact in glioblastoma. Neuro Oncol. 18, 195–205 (2016)." href="/articles/nrneurol.2017.64#ref-CR113" id="ref-link-section-d70610963e2260">113</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 114" title="Wintterle, S. et al. Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res. 63, 7462–7467 (2003)." href="/articles/nrneurol.2017.64#ref-CR114" id="ref-link-section-d70610963e2263">114</a></sup>. Moreover, inhibition of this pathway results in substantial antitumour activity in rodent models of glioma<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Antonios, J. P. et al. PD-1 blockade enhances the vaccination-induced immune response in glioma. JCI Insight 1, e87059 (2016)." href="/articles/nrneurol.2017.64#ref-CR28" id="ref-link-section-d70610963e2267">28</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 115" title="Reardon, D. A. et al. Glioblastoma eradication following immune checkpoint blockade in an orthotopic, immunocompetent model. Cancer Immunol. Res. 4, 124–135 (2016)." href="/articles/nrneurol.2017.64#ref-CR115" id="ref-link-section-d70610963e2270">115</a></sup>, and PD1 inhibition in combination with DC vaccination prolonged the survival of glioma-bearing mice to a greater extent than treatment with either agent alone. Immune checkpoint inhibitors have also proven active against brain metastases in clinical trials<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Hartmann, C. et al. Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol. 120, 707–718 (2010)." href="/articles/nrneurol.2017.64#ref-CR7" id="ref-link-section-d70610963e2274">7</a></sup>, and a report published in 2016 documented clinically significant responses to the PD1 inhibitor nivolumab in two patients with recurrent glioblastoma who also had germline biallelic mismatch repair deficiency, providing proof of the concept that this therapeutic strategy is feasible in human CNS tumours<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 108" title="Preusser, M., Lim, M., Hafler, D. A., Reardon, D. A. & Sampson, J. H. Prospects of immune checkpoint modulators in the treatment of glioblastoma. Nat. Rev. Neurol. 11, 504–514 (2015)." href="/articles/nrneurol.2017.64#ref-CR108" id="ref-link-section-d70610963e2278">108</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 116" title="Bouffet, E. et al. Immune checkpoint inhibition for hypermutant glioblastoma multiforme resulting from germline biallelic mismatch repair deficiency. J. Clin. Oncol. 34, 2206–2211 (2016)." href="/articles/nrneurol.2017.64#ref-CR116" id="ref-link-section-d70610963e2281">116</a></sup>. Large clinical trials are currently evaluating the efficacy of immune checkpoint inhibitors in patients with newly diagnosed and recurrent glioblastoma<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 117" title="Weiss, T., Weller, M. & Roth, P. Immunotherapy for glioblastoma: concepts and challenges. Curr. Opin. Neurol. 28, 639–646 (2015)." href="/articles/nrneurol.2017.64#ref-CR117" id="ref-link-section-d70610963e2285">117</a></sup>.</p><p>Current preclinical research is not only evaluating additional immune checkpoint inhibitors, but also identifying checkpoint receptors that activate immune responses and so could be targeted using agonistic antibodies. Early preclinical data indicate that the co-stimulatory molecule OX40 (also known as CD134 or tumour necrosis factor receptor superfamily member 4) and its ligand OX40L (also known as CD252 or tumour necrosis factor ligand superfamily member 4) are involved in T-cell activation in glioblastoma<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 118" title="Shibahara, I. et al. OX40 ligand expressed in glioblastoma modulates adaptive immunity depending on the microenvironment: a clue for successful immunotherapy. Mol. Cancer 14, 41 (2015)." href="/articles/nrneurol.2017.64#ref-CR118" id="ref-link-section-d70610963e2292">118</a></sup>. Future research will show whether immune checkpoint modulators are capable of synergistically increasing the antitumour response of vaccination strategies against glioma in the clinical setting.</p><p><b><i>TGFβ inhibitors.</i></b> Neutralizing the biological activity of TGFβ, the master immunosuppressive cytokine associated with glioma, also presents an option to improve the activity of vaccines for glioma treatment. The utility of this approach has been demonstrated in mouse models of glioma, in which treatment with TGFβ inhibitors enhanced the therapeutic efficacy of peptide vaccines and promoted CD70-mediated tumour rejection<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Ueda, R. et al. Systemic inhibition of transforming growth factor-β in glioma-bearing mice improves the therapeutic efficacy of glioma-associated antigen peptide vaccines. Clin. Cancer Res. 15, 6551–6559 (2009)." href="/articles/nrneurol.2017.64#ref-CR27" id="ref-link-section-d70610963e2302">27</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 119" title="Aulwurm, S., Wischhusen, J., Friese, M., Borst, J. & Weller, M. Immune stimulatory effects of CD70 override CD70-mediated immune cell apoptosis in rodent glioma models and confer long-lasting antiglioma immunity in vivo. Int. J. Cancer 118, 1728–1735 (2006)." href="/articles/nrneurol.2017.64#ref-CR119" id="ref-link-section-d70610963e2305">119</a></sup>.</p><p>In humans, inhibition of TGFβ activity alone, using receptor tyrosine kinase inhibitors such as galunisertib, showed little activity in patients with glioma at first relapse<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 120" title="Brandes, A. A. et al. A phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma. Neuro Oncol. 18, 1146–1156 (2016)." href="/articles/nrneurol.2017.64#ref-CR120" id="ref-link-section-d70610963e2312">120</a></sup>. Continuous dosing of such drugs is poorly tolerated, which necessitated a 2 weeks on, 2 weeks off dosing regimen in the clinical trial setting<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 120" title="Brandes, A. A. et al. A phase II randomized study of galunisertib monotherapy or galunisertib plus lomustine compared with lomustine monotherapy in patients with recurrent glioblastoma. Neuro Oncol. 18, 1146–1156 (2016)." href="/articles/nrneurol.2017.64#ref-CR120" id="ref-link-section-d70610963e2316">120</a></sup> that might be insufficient to inhibit the TGFβ–SMAD pathway to a relevant extent. Combinations of TGFβ inhibitors and a specific immunotherapy approach might still be worth exploring, however. For instance, the dosing of TGFβ inhibitors could be limited to specific weeks of active vaccine treatment.</p><p><b><i>Immunometabolic pathway inhibitors.</i></b> The immunosuppressive microenvironment surrounding glioma is further maintained by metabolization of tryptophan, an essential amino acid. Tryptophan is cleaved by dioxygenases such as indoleamine-2,3-dioxygenase (IDO) or tryptophan-2,3-dioxygenase (TDO), resulting in several metabolites, but mainly kynurenine. Depletion of tryptophan and high levels of kynurenine both lead to impaired T-cell activation <i>in vitro</i><sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 121" title="Platten, M., Weller, M. & Wick, W. Shaping the glioma immune microenvironment through tryptophan metabolism. CNS Oncol. 1, 99–106 (2012)." href="/articles/nrneurol.2017.64#ref-CR121" id="ref-link-section-d70610963e2327">121</a></sup>. Hence, the addition of inhibitors of IDO, TDO or the aryl hydrocarbon receptor (AHR; a receptor for kynurenine that transduces its immunosuppressive signals to T cells and myeloid cells), could help to increase the activity of immune responses following vaccination<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 122" title="Opitz, C. A. et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197–203 (2011)." href="/articles/nrneurol.2017.64#ref-CR122" id="ref-link-section-d70610963e2331">122</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 123" title="Wainwright, D. A. et al. Durable therapeutic efficacy utilizing combinatorial blockade against IDO, CTLA-4, and PD-L1 in mice with brain tumors. Clin. Cancer Res. 20, 5290–5301 (2014)." href="/articles/nrneurol.2017.64#ref-CR123" id="ref-link-section-d70610963e2334">123</a></sup>. Similarly, inhibition of the activity of signal transducer and activator of transcription 3 (STAT3), which is a central regulator of various glioma-derived immunosuppressive mechanisms, might represent a therapeutic strategy to overcome the immunosuppressive tumour microenvironment<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 124" title="Ferguson, S. D., Srinivasan, V. M. & Heimberger, A. B. The role of STAT3 in tumor-mediated immune suppression. J. Neurooncol. 123, 385–394 (2015)." href="/articles/nrneurol.2017.64#ref-CR124" id="ref-link-section-d70610963e2338">124</a></sup>. Such concepts are only at an early stage of clinical development; however, a phase I study in patients with recurrent malignant glioma or brain metastasis from melanoma is ongoing<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 125" title="US National Library of Medicine. ClinicalTrials.gov 
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 (2016)." href="/articles/nrneurol.2017.64#ref-CR125" id="ref-link-section-d70610963e2342">125</a></sup>.</p><p><b><i>Targeting regulatory T cells.</i></b> Patients with glioblastoma are profoundly immunosuppressed, at least partly as a result of an excessive number of immunosuppressive myeloid-derived suppressor cells (MDSC) and regulatory T cells (T<sub>reg</sub> cells)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 126" title="Fecci, P. E. et al. Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res. 66, 3294–3302 (2006)." href="/articles/nrneurol.2017.64#ref-CR126" id="ref-link-section-d70610963e2353">126</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 127" title="El Andaloussi, A. & Lesniak, M. S. An increase in CD4+CD25+FOXP3+ regulatory T cells in tumor-infiltrating lymphocytes of human glioblastoma multiforme. J. Neurooncol. 8, 234–243 (2006)." href="/articles/nrneurol.2017.64#ref-CR127" id="ref-link-section-d70610963e2356">127</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 128" title="Grauer, O. M. et al. CD4+FoxP3+ regulatory T cells gradually accumulate in gliomas during tumor growth and efficiently suppress antiglioma immune responses in vivo. Int. J. Cancer. 121, 95–105 (2007)." href="/articles/nrneurol.2017.64#ref-CR128" id="ref-link-section-d70610963e2359">128</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 129" title="Raychaudhuri, B. et al. Myeloid-derived suppressor cell accumulation and function in patients with newly diagnosed glioblastoma. Neuro Oncol. 13, 591–599 (2011)." href="/articles/nrneurol.2017.64#ref-CR129" id="ref-link-section-d70610963e2362">129</a></sup>. Key features of this immunosuppressive phenotype can be reversed by eliminating T<sub>reg</sub> cells<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 126" title="Fecci, P. E. et al. Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res. 66, 3294–3302 (2006)." href="/articles/nrneurol.2017.64#ref-CR126" id="ref-link-section-d70610963e2368">126</a></sup>. When T<sub>reg</sub> cells are depleted <i>in vitro</i>, T-cell proliferation and cytokine secretion return to normal levels<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 126" title="Fecci, P. E. et al. Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma. Cancer Res. 66, 3294–3302 (2006)." href="/articles/nrneurol.2017.64#ref-CR126" id="ref-link-section-d70610963e2378">126</a></sup>; <i>in vivo</i> depletion of T<sub>reg</sub> cells 1 week after tumour implantation prolonged the survival of mice inoculated with glioma cells, demonstrating not only that T<sub>reg</sub>-mediated immunosuppression is reversible, but also that T<sub>reg</sub> impairment positively influences antitumour immunity<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 130" title="El Andaloussi, A., Han, Y. & Lesniak, M. S. Prolongation of survival following depletion of CD4+CD25+ regulatory T cells in mice with experimental brain tumors. J. Neurosurg. 105, 430–437 (2006)." href="/articles/nrneurol.2017.64#ref-CR130" id="ref-link-section-d70610963e2392">130</a></sup>.</p><p>Previous attempts to eliminate T<sub>reg</sub> cells have had mixed outcomes<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 131" title="Morse, M. A. et al. Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines. Blood 112, 610–618 (2008)." href="/articles/nrneurol.2017.64#ref-CR131" id="ref-link-section-d70610963e2401">131</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 132" title="Jacobs, J. F. et al. Dendritic cell vaccination in combination with anti-CD25 monoclonal antibody treatment: a phase I/II study in metastatic melanoma patients. Clin. Cancer Res. 16, 5067–5078 (2010)." href="/articles/nrneurol.2017.64#ref-CR132" id="ref-link-section-d70610963e2404">132</a></sup>, possibly because T<sub>reg</sub> depletion was not employed in the unique host environment that exists after therapeutic temozolomide-induced lymphodepletion. These strategies might also have failed because they employed the IL-2 moiety itself to target T<sub>reg</sub> cells. This method would result in indiscriminate targeting of low-affinity IL-2βγ receptors, which are expressed on a broad subset of immune cells, including memory T cells. Alternative strategies that employ IL-2Rα-targeted immunotoxins result in rapid and indiscriminate killing of all IL-2Rα-expressing cells, which might include recently activated, vaccine-induced effector T cells. In marked contrast, IL-2Rα-specific antibodies lacking the bound immunotoxin eliminate T<sub>reg</sub> cells while having no effect on effector T cells in lymphopenic mice<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 133" title="Attia, P. et al. Selective elimination of human regulatory T lymphocytes in vitro with the recombinant immunotoxin LMB-2. J. Immunother. 29, 208–214 (2006)." href="/articles/nrneurol.2017.64#ref-CR133" id="ref-link-section-d70610963e2415">133</a></sup>.</p></div></div></section><section data-title="Conclusions and future perspectives"><div class="c-article-section" id="Sec5-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec5">Conclusions and future perspectives</h2><div class="c-article-section__content" id="Sec5-content"><p>Glioblastoma remains one of the most-studied tumours in the context of cancer-associated immunosuppression. Numerous soluble mediators and cell-based pathways of immunosuppression were first delineated in glioblastoma, and these observations collectively support further efforts at establishing efficacious antitumour immunotherapies. Although proof of efficacy is not yet available for any of the glioma-specific peptide vaccines currently in clinical development, the addition of immune checkpoint inhibitors or other approaches that boost immune responses in vaccinated patients might ultimately be able to demonstrate that active immunotherapy can control the growth of human intracranial neoplasms.</p><p>Meanwhile, the clinical development of immunotherapy for glioblastoma could be aided by collective efforts to introduce measures of quality control and standardization of inclusion and exclusion criteria, as well as standardized response and other efficacy criteria in immunotherapy trials. The iRANO (Immunotherapy Response Assessment in Neuro-Oncology) criteria, which essentially caution against the premature assumption of inefficacy or treatment failure in early phase clinical trials of immunotherapy<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 134" title="Okada, H. et al. Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol. 16, e534–e542 (2015)." href="/articles/nrneurol.2017.64#ref-CR134" id="ref-link-section-d70610963e2430">134</a></sup>, are just a first step in this direction. The identification of tumour or serum biomarkers that predict response or progression of glioblastoma is needed to improve the conduct and efficiency of clinical trials. Such efforts will require international collaboration involving all the major organizations and disciplines involved in the orchestration of care for patients with brain tumours.</p></div></div></section><section data-title="Publisher's note"><div class="c-article-section" id="Sec6-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec6">Publisher's note</h2><div class="c-article-section__content" id="Sec6-content"><p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></div></div></section> </div> <div> <div id="MagazineFulltextArticleBodySuffix"><section aria-labelledby="Bib1" data-title="References"><div class="c-article-section" id="Bib1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Bib1">References</h2><div class="c-article-section__content" id="Bib1-content"><div data-container-section="references"><ol class="c-article-references" data-track-component="outbound reference" data-track-context="references section"><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="1"><p class="c-article-references__text" id="ref-CR1">Nduom, E. 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data-counter="143"><p class="c-article-references__text" id="ref-CR143">US National Library of Medicine. <i>ClinicalTrials.gov</i> <a href="https://clinicaltrials.gov/ct2/show/NCT02455557" data-track="click_references" data-track-action="external reference" data-track-value="external reference" data-track-label="https://clinicaltrials.gov/ct2/show/NCT02455557">https://clinicaltrials.gov/ct2/show/NCT02455557</a> (2017).</p></li></ol><p class="c-article-references__download u-hide-print"><a data-track="click" data-track-action="download citation references" data-track-label="link" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/nrneurol.2017.64?format=refman&flavour=references">Download references<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p></div></div></div></section></div><section data-title="Acknowledgements"><div class="c-article-section" id="Ack1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Ack1">Acknowledgements</h2><div class="c-article-section__content" id="Ack1-content"><p>The authors' research work is supported by grants from the Canton of Zurich HSM-2 (Hochspezialisierte Medizin 2) programme, the German Research Fund (Deutsche Forschungsgemeinschaft), the Swiss National Science Foundation and the Swiss Cancer League (all to M.W. and P.R.).</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Department of Neurology and Brain Tumour Centre, University Hospital and University of Zurich, Frauenklinikstrasse 26, Zurich, 8091, Switzerland</p><p class="c-article-author-affiliation__authors-list">Michael Weller & Patrick Roth</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Department of Medicine I and Comprehensive Cancer Centre CNS Unit, Medical University of Vienna, Waehringer Guertel 18–20, Vienna, 1090, Austria</p><p class="c-article-author-affiliation__authors-list">Matthias Preusser</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Neurology Clinic, Heidelberg University Medical Centre and Neuro-oncology Programme, National Centre for Tumour Diseases Heidelberg, Im Neuenheimer Feld (INF) 400, Heidelberg, 69120, Germany</p><p class="c-article-author-affiliation__authors-list">Wolfgang Wick & Michael Platten</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">Dana-Farber Cancer Institute, 450 Brookline Avenue, D-2134, Boston, 02215–5450, Massachusetts, USA</p><p class="c-article-author-affiliation__authors-list">David A. Reardon</p></li><li id="Aff5"><p class="c-article-author-affiliation__address">Neurology Clinic, Mannheim Medical Centre, Heidelberg University and Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumour Immunology, German Cancer Research Centre, Im Neuenheimer Feld (INF) 280, Heidelberg, 69120, Germany</p><p class="c-article-author-affiliation__authors-list">Michael Platten</p></li><li id="Aff6"><p class="c-article-author-affiliation__address">Department of Neurosurgery, Duke University Medical Center, 200 Trent Drive, Duke South, Blue Zone, 1st Floor, Room 1554, Durham, 27710, North Carolina, USA</p><p class="c-article-author-affiliation__authors-list">John H. Sampson</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Michael-Weller-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Michael Weller</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=Michael%20Weller" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Michael%20Weller" data-track="click" data-track-action="author link - 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Sampson</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?author=John%20H.%20Sampson" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=John%20H.%20Sampson" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22John%20H.%20Sampson%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li></ol></div><h3 class="c-article__sub-heading" id="contributions">Contributions</h3><p>All authors wrote the manuscript, researched data for the article, undertook review or editing of the manuscript before submission and contributed substantially to discussions of the article content.</p><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding author</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:michael.weller@usz.ch">Michael Weller</a>.</p></div></div></section><section data-title="Ethics declarations"><div class="c-article-section" id="ethics-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="ethics">Ethics declarations</h2><div class="c-article-section__content" id="ethics-content"> <h3 class="c-article__sub-heading">Competing interests</h3> <p>The authors declare that M.W. has received research grants from Acceleron, Actelion, Bayer, Isarna, Merck Sharp & Dohme, Merck EMD (Emanuel Merck, Darmstadt), Novocure, Piqur and Roche and honoraria for lectures, advisory board participation or consulting from Bristol-Myers Squibb, Celldex, Immunocellular Therapeutics, Isarna, Magforce, Merck Sharp & Dohme, Merck EMD, Northwest Biotherapeutics, Novocure, Pfizer, Roche, Teva and Tocagen. M. Preusser has received research support from Böhringer-Ingelheim, GlaxoSmithKline, Merck Sharp & Dohme and Roche, as well as honoraria for lectures, advisory board participation or consulting from Bristol-Myers Squibb, CMC Contrast, Gerson Lehrman Group, GlaxoSmithKline, Mundipharma, Novartis and Roche. D.A.R. has received research grants from Celldex Therapeutics, Incyte and Midatech, as well as honoraria for lectures, advisory board participation or consulting from Abbvie, Amgen, Bristol-Myers Squibb, Cavion, Celldex Therapeutics, EMD Serono, Genentech (Roche), Inovio, Juno Pharmaceuticals, Merck & Co, Midatech, Momenta Pharmaceuticals, Novartis, Novocure, Oxigene, Regeneron, and Stemline Therapeutics. M. Platten has received research support from Merck and Novartis, as well as honoraria for lectures, consultation or advisory board participation from Alexion, Bayer, Genentech (Roche), Merck & Co, Medac, Miltenyi Biotec, Novartis and Teva. M. Platten also holds patents on isocitrate dehydrogenase vaccines and aryl hydrocarbon receptor inhibition. P.R. has received research support from Merck Sharp & Dohme and honoraria for lectures or advisory board participation from Merck Sharp & Dohme, Molecular Partners, Novartis and Roche. W.W. has received research funding from Apogenix, Böhringer-Ingelheim, Genentech (Roche), Merck Sharp & Dohme and Pfizer, as well as honoraria for participating in a speaker's bureau for Merck Sharp & Dohme and consulting for Genentech (Roche). J.H.S. declares that he is an employee of Annias, a shareholder in Annias and Istari, and has received honoraria for consulting from Celldex, BrainLAB and Medicenna, as well as licensing fees from Celldex.</p> </div></div></section><section data-title="PowerPoint slides"><div class="c-article-section" id="Sec7-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec7">PowerPoint slides</h2><div class="c-article-section__content" id="Sec7-content"><div data-test="supplementary-info"><div id="figshareContainer" class="c-article-figshare-container" data-test="figshare-container"></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM103"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="powerpoint slide for fig. 1" 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href="https://static-content.springer.com/esm/art%3A10.1038%2Fnrneurol.2017.64/MediaObjects/41582_2017_BFnrneurol201764_MOESM107_ESM.ppt" data-supp-info-image="">PowerPoint slide for Table 1</a></h3></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM108"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="powerpoint slide for table 2" href="https://static-content.springer.com/esm/art%3A10.1038%2Fnrneurol.2017.64/MediaObjects/41582_2017_BFnrneurol201764_MOESM108_ESM.ppt" data-supp-info-image="">PowerPoint slide for Table 2</a></h3></div></div></div></div></section><section data-title="Rights and permissions"><div class="c-article-section" id="rightslink-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="rightslink">Rights and permissions</h2><div class="c-article-section__content" 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id="citeas">Cite this article</h3><p class="c-bibliographic-information__citation">Weller, M., Roth, P., Preusser, M. <i>et al.</i> Vaccine-based immunotherapeutic approaches to gliomas and beyond. <i>Nat Rev Neurol</i> <b>13</b>, 363–374 (2017). https://doi.org/10.1038/nrneurol.2017.64</p><p class="c-bibliographic-information__download-citation u-hide-print"><a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/nrneurol.2017.64?format=refman&flavour=citation">Download citation<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p><ul class="c-bibliographic-information__list" data-test="publication-history"><li class="c-bibliographic-information__list-item"><p>Published<span 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