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Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models2. Arm A of Phase I trial no. \n NCT04196413\n \n (ref. 3) administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels (DL1, 1 × 106 kg−1; DL2, 3 × 106 kg−1) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10–30 × 106 GD2-CART). Primary objectives were manufacturing feasibility, tolerability and the identification of maximally tolerated IV dose. Secondary objectives included preliminary assessments of benefit. Thirteen patients enroled, with 11 receiving IV GD2-CART on study (n = 3 DL1 (3 DIPG); n = 8 DL2 (6 DIPG, 2 sDMG)). GD2-CART manufacture was successful for all patients. No dose-limiting toxicities occurred on DL1, but three patients experienced dose-limiting cytokine release syndrome on DL2, establishing DL1 as the maximally tolerated IV dose. Nine patients received ICV infusions, with no dose-limiting toxicities. All patients exhibited tumour inflammation-associated neurotoxicity, safely managed with intensive monitoring and care. Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months since enrolment. Nine patients demonstrated neurological benefit, as measured by a protocol-directed clinical improvement score. Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG. We evaluated the use of chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) for H3K27M+ diffuse midline glioma (DMG), finding that intravenous administration of GD2-CART, followed by intracranial infusions, induced tumour regressions and neurological improvements in patients with H3K27M-mutant pontine or spinal DMG.","datePublished":"2024-11-13T00:00:00Z","dateModified":"2024-11-13T00:00:00Z","pageStart":"1","pageEnd":"8","license":"http://creativecommons.org/licenses/by-nc-nd/4.0/","sameAs":"https://doi.org/10.1038/s41586-024-08171-9","keywords":["Cancer immunotherapy","CNS cancer","Science","Humanities and Social Sciences","multidisciplinary"],"image":["https://media.springernature.com/lw1200/springer-static/image/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig1_HTML.png","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig2_HTML.png","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig3_HTML.png"],"isPartOf":{"name":"Nature","issn":["1476-4687","0028-0836"],"@type":["Periodical"]},"publisher":{"name":"Nature Publishing Group UK","logo":{"url":"https://www.springernature.com/app-sn/public/images/logo-springernature.png","@type":"ImageObject"},"@type":"Organization"},"author":[{"name":"Michelle Monje","url":"http://orcid.org/0000-0002-3547-237X","affiliation":[{"name":"Stanford University","address":{"name":"Department of Neurology and Neurological Sciences, Stanford University, Stanford, USA","@type":"PostalAddress"},"@type":"Organization"},{"name":"Stanford University","address":{"name":"Division of Pediatric Hematology/Oncology/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, USA","@type":"PostalAddress"},"@type":"Organization"},{"name":"Stanford University","address":{"name":"Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, USA","@type":"PostalAddress"},"@type":"Organization"},{"name":"Stanford University","address":{"name":"Department of Neurosurgery, Stanford University, Stanford, USA","@type":"PostalAddress"},"@type":"Organization"},{"name":"Stanford University","address":{"name":"Department of Pathology, Stanford University, Stanford, USA","@type":"PostalAddress"},"@type":"Organization"},{"name":"Stanford University","address":{"name":"Howard Hughes Medical Institute, Stanford University, Stanford, USA","@type":"PostalAddress"},"@type":"Organization"}],"email":"mmonje@stanford.edu","@type":"Person"},{"name":"Jasia Mahdi","affiliation":[{"name":"Stanford University","address":{"name":"Department of Neurology and Neurological Sciences, Stanford University, Stanford, USA","@type":"PostalAddress"},"@type":"Organization"},{"name":"Stanford University","address":{"name":"Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Robbie Majzner","url":"http://orcid.org/0000-0001-6969-8011","affiliation":[{"name":"Stanford University","address":{"name":"Division of Pediatric Hematology/Oncology/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, USA","@type":"PostalAddress"},"@type":"Organization"},{"name":"Stanford University","address":{"name":"Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Kristen W. 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Davis","url":"http://orcid.org/0000-0002-7182-2592","affiliation":[{"name":"Stanford University","address":{"name":"Division of Pediatric Hematology/Oncology/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, USA","@type":"PostalAddress"},"@type":"Organization"},{"name":"Stanford University","address":{"name":"Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Steven A. 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Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models2. Arm A of Phase I trial no. NCT04196413 (ref.&nbsp;3) administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels (DL1, 1 × 106 kg−1; DL2, 3 × 106 kg−1) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10–30 × 106 GD2-CART). Primary objectives were manufacturing feasibility, tolerability and the identification of maximally tolerated IV dose. Secondary objectives included preliminary assessments of benefit. Thirteen patients enroled, with 11 receiving IV GD2-CART on study (n = 3 DL1 (3 DIPG); n = 8 DL2 (6 DIPG, 2 sDMG)). GD2-CART manufacture was successful for all patients. No dose-limiting toxicities occurred on DL1, but three patients experienced dose-limiting cytokine release syndrome on DL2, establishing DL1 as the maximally tolerated IV dose. Nine patients received ICV infusions, with no dose-limiting toxicities. All patients exhibited tumour inflammation-associated neurotoxicity, safely managed with intensive monitoring and care. Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months since enrolment. Nine patients demonstrated neurological benefit, as measured by a protocol-directed clinical improvement score. Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG. We evaluated the use of chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) for H3K27M+ diffuse midline glioma (DMG), finding that intravenous administration of GD2-CART, followed by intracranial infusions, induced tumour regressions and neurological improvements in patients with H3K27M-mutant pontine or spinal DMG."/> <meta name="prism.issn" content="1476-4687"/> <meta name="prism.publicationName" content="Nature"/> <meta name="prism.publicationDate" content="2024-11-13"/> <meta name="prism.section" content="OriginalPaper"/> <meta name="prism.startingPage" content="1"/> <meta name="prism.endingPage" content="8"/> <meta name="prism.copyright" content="2024 The Author(s)"/> <meta name="prism.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="prism.url" content="https://www.nature.com/articles/s41586-024-08171-9"/> <meta name="prism.doi" content="doi:10.1038/s41586-024-08171-9"/> <meta name="citation_pdf_url" content="https://www.nature.com/articles/s41586-024-08171-9.pdf"/> <meta name="citation_fulltext_html_url" content="https://www.nature.com/articles/s41586-024-08171-9"/> <meta name="citation_journal_title" content="Nature"/> <meta name="citation_journal_abbrev" content="Nature"/> <meta name="citation_publisher" content="Nature Publishing Group"/> <meta name="citation_issn" content="1476-4687"/> <meta name="citation_title" content="Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline gliomas"/> <meta name="citation_online_date" content="2024/11/13"/> <meta name="citation_firstpage" content="1"/> <meta name="citation_lastpage" content="8"/> <meta name="citation_article_type" content="Article"/> <meta name="citation_fulltext_world_readable" content=""/> <meta name="citation_language" content="en"/> <meta name="dc.identifier" content="doi:10.1038/s41586-024-08171-9"/> <meta name="DOI" content="10.1038/s41586-024-08171-9"/> <meta name="size" content="203079"/> <meta name="citation_doi" content="10.1038/s41586-024-08171-9"/> <meta name="citation_springer_api_url" content="http://api.springer.com/xmldata/jats?q=doi:10.1038/s41586-024-08171-9&api_key="/> <meta name="description" content="H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2&nbsp;(ref. 1). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models2. Arm A of Phase I trial no. NCT04196413 (ref.&nbsp;3) administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels (DL1, 1 × 106 kg−1; DL2, 3 × 106 kg−1) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10–30 × 106 GD2-CART). Primary objectives were manufacturing feasibility, tolerability and the identification of maximally tolerated IV dose. Secondary objectives included preliminary assessments of benefit. Thirteen patients enroled, with 11 receiving IV GD2-CART on study (n = 3 DL1 (3 DIPG); n = 8 DL2 (6 DIPG, 2 sDMG)). GD2-CART manufacture was successful for all patients. No dose-limiting toxicities occurred on DL1, but three patients experienced dose-limiting cytokine release syndrome on DL2, establishing DL1 as the maximally tolerated IV dose. Nine patients received ICV infusions, with no dose-limiting toxicities. All patients exhibited tumour inflammation-associated neurotoxicity, safely managed with intensive monitoring and care. Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months since enrolment. Nine patients demonstrated neurological benefit, as measured by a protocol-directed clinical improvement score. Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG. We evaluated the use of chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) for H3K27M+ diffuse midline glioma (DMG), finding that intravenous administration of GD2-CART, followed by intracranial infusions, induced tumour regressions and neurological improvements in patients with H3K27M-mutant pontine or spinal DMG."/> <meta name="dc.creator" content="Monje, Michelle"/> <meta name="dc.creator" content="Mahdi, Jasia"/> <meta name="dc.creator" content="Majzner, Robbie"/> <meta name="dc.creator" content="Yeom, Kristen W."/> <meta name="dc.creator" content="Schultz, Liora M."/> <meta name="dc.creator" content="Richards, Rebecca M."/> <meta name="dc.creator" content="Barsan, Valentin"/> <meta name="dc.creator" content="Song, Kun-Wei"/> <meta name="dc.creator" content="Kamens, Jen"/> <meta name="dc.creator" content="Baggott, Christina"/> <meta name="dc.creator" content="Kunicki, Michael"/> <meta name="dc.creator" content="Rietberg, Skyler P."/> <meta name="dc.creator" content="Lim, Alexandria Sung"/> <meta name="dc.creator" content="Reschke, Agnes"/> <meta name="dc.creator" content="Mavroukakis, Sharon"/> <meta name="dc.creator" content="Egeler, Emily"/> <meta name="dc.creator" content="Moon, Jennifer"/> <meta name="dc.creator" content="Patel, Shabnum"/> <meta name="dc.creator" content="Chinnasamy, Harshini"/> <meta name="dc.creator" content="Erickson, Courtney"/> <meta name="dc.creator" content="Jacobs, Ashley"/> <meta name="dc.creator" content="Duh, Allison K."/> <meta name="dc.creator" content="Tunuguntla, Ramya"/> <meta name="dc.creator" content="Klysz, Dorota Danuta"/> <meta name="dc.creator" content="Fowler, Carley"/> <meta name="dc.creator" content="Green, Sean"/> <meta name="dc.creator" content="Beebe, Barbara"/> <meta name="dc.creator" content="Carr, Casey"/> <meta name="dc.creator" content="Fujimoto, Michelle"/> <meta name="dc.creator" content="Brown, Annie Kathleen"/> <meta name="dc.creator" content="Petersen, Ann-Louise G."/> <meta name="dc.creator" content="McIntyre, Catherine"/> <meta name="dc.creator" content="Siddiqui, Aman"/> <meta name="dc.creator" content="Lepori-Bui, Nadia"/> <meta name="dc.creator" content="Villar, Katlin"/> <meta name="dc.creator" content="Pham, Kymhuynh"/> <meta name="dc.creator" content="Bove, Rachel"/> <meta name="dc.creator" content="Musa, Eric"/> <meta name="dc.creator" content="Reynolds, Warren D."/> <meta name="dc.creator" content="Kuo, Adam"/> <meta name="dc.creator" content="Prabhu, Snehit"/> <meta name="dc.creator" content="Rasmussen, Lindsey"/> <meta name="dc.creator" content="Cornell, Timothy T."/> <meta name="dc.creator" content="Partap, Sonia"/> <meta name="dc.creator" content="Fisher, Paul G."/> <meta name="dc.creator" content="Campen, Cynthia J."/> <meta name="dc.creator" content="Grant, Gerald"/> <meta name="dc.creator" content="Prolo, Laura"/> <meta name="dc.creator" content="Ye, Xiaobu"/> <meta name="dc.creator" content="Sahaf, Bita"/> <meta name="dc.creator" content="Davis, Kara L."/> <meta name="dc.creator" content="Feldman, Steven A."/> <meta name="dc.creator" content="Ramakrishna, Sneha"/> <meta name="dc.creator" content="Mackall, Crystal"/> <meta name="dc.subject" content="Cancer immunotherapy"/> <meta name="dc.subject" content="CNS cancer"/> <meta name="citation_reference" content="Mount, C. 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data-test="article-category">Article</li> <li class="c-article-identifiers__item"> <a href="https://www.springernature.com/gp/open-research/about/the-fundamentals-of-open-access-and-open-research" data-track="click" data-track-action="open access" data-track-label="link" class="u-color-open-access" data-test="open-access">Open access</a> </li> <li class="c-article-identifiers__item">Published: <time datetime="2024-11-13">13 November 2024</time></li> </ul> <h1 class="c-article-title" data-test="article-title" data-article-title="">Intravenous and intracranial GD2-CAR T cells for H3K27M<sup>+</sup> diffuse midline gliomas</h1> <ul class="c-article-author-list c-article-author-list--long" 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-Michelle-Monje-Aff1-Aff2-Aff3-Aff4-Aff5-Aff6" data-author-popup="auth-Michelle-Monje-Aff1-Aff2-Aff3-Aff4-Aff5-Aff6" data-author-search="Monje, Michelle" data-corresp-id="c1">Michelle Monje<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><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-3547-237X"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-3547-237X</a></span><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff2">2</a>,<a href="#Aff3">3</a>,<a href="#Aff4">4</a>,<a href="#Aff5">5</a>,<a href="#Aff6">6</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-Jasia-Mahdi-Aff1-Aff3" data-author-popup="auth-Jasia-Mahdi-Aff1-Aff3" data-author-search="Mahdi, Jasia">Jasia Mahdi</a><sup class="u-js-hide"><a href="#Aff1">1</a>,<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-Robbie-Majzner-Aff2-Aff3" data-author-popup="auth-Robbie-Majzner-Aff2-Aff3" data-author-search="Majzner, Robbie">Robbie Majzner</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0001-6969-8011"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0001-6969-8011</a></span><sup class="u-js-hide"><a href="#Aff2">2</a>,<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-Kristen_W_-Yeom-Aff1-Aff4-Aff7" data-author-popup="auth-Kristen_W_-Yeom-Aff1-Aff4-Aff7" data-author-search="Yeom, Kristen W.">Kristen W. Yeom</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0001-9860-3368"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0001-9860-3368</a></span><sup class="u-js-hide"><a href="#Aff1">1</a>,<a href="#Aff4">4</a>,<a href="#Aff7">7</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-Liora_M_-Schultz-Aff2-Aff3" data-author-popup="auth-Liora_M_-Schultz-Aff2-Aff3" data-author-search="Schultz, Liora M.">Liora M. Schultz</a><sup class="u-js-hide"><a href="#Aff2">2</a>,<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-Rebecca_M_-Richards-Aff2-Aff3" data-author-popup="auth-Rebecca_M_-Richards-Aff2-Aff3" data-author-search="Richards, Rebecca M.">Rebecca M. Richards</a><sup class="u-js-hide"><a href="#Aff2">2</a>,<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-Valentin-Barsan-Aff2-Aff3" data-author-popup="auth-Valentin-Barsan-Aff2-Aff3" data-author-search="Barsan, Valentin">Valentin Barsan</a><sup class="u-js-hide"><a href="#Aff2">2</a>,<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-Kun_Wei-Song-Aff1-Aff3" data-author-popup="auth-Kun_Wei-Song-Aff1-Aff3" data-author-search="Song, Kun-Wei">Kun-Wei Song</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-4472-230X"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-4472-230X</a></span><sup class="u-js-hide"><a href="#Aff1">1</a>,<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-Jen-Kamens-Aff2-Aff3" data-author-popup="auth-Jen-Kamens-Aff2-Aff3" data-author-search="Kamens, Jen">Jen Kamens</a><sup class="u-js-hide"><a href="#Aff2">2</a>,<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-Christina-Baggott-Aff3" data-author-popup="auth-Christina-Baggott-Aff3" data-author-search="Baggott, Christina">Christina Baggott</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-Michael-Kunicki-Aff3" data-author-popup="auth-Michael-Kunicki-Aff3" data-author-search="Kunicki, Michael">Michael Kunicki</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0001-6630-6289"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0001-6630-6289</a></span><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-Skyler_P_-Rietberg-Aff3" data-author-popup="auth-Skyler_P_-Rietberg-Aff3" data-author-search="Rietberg, Skyler P.">Skyler P. Rietberg</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-Alexandria_Sung-Lim-Aff3" data-author-popup="auth-Alexandria_Sung-Lim-Aff3" data-author-search="Lim, Alexandria Sung">Alexandria Sung Lim</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-Agnes-Reschke-Aff2-Aff3" data-author-popup="auth-Agnes-Reschke-Aff2-Aff3" data-author-search="Reschke, Agnes">Agnes Reschke</a><sup class="u-js-hide"><a href="#Aff2">2</a>,<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-Sharon-Mavroukakis-Aff3" data-author-popup="auth-Sharon-Mavroukakis-Aff3" data-author-search="Mavroukakis, Sharon">Sharon Mavroukakis</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-Emily-Egeler-Aff3" data-author-popup="auth-Emily-Egeler-Aff3" data-author-search="Egeler, Emily">Emily Egeler</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0001-5173-0335"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0001-5173-0335</a></span><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-Jennifer-Moon-Aff3" data-author-popup="auth-Jennifer-Moon-Aff3" data-author-search="Moon, Jennifer">Jennifer Moon</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-Shabnum-Patel-Aff3" data-author-popup="auth-Shabnum-Patel-Aff3" data-author-search="Patel, Shabnum">Shabnum Patel</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-Harshini-Chinnasamy-Aff3" data-author-popup="auth-Harshini-Chinnasamy-Aff3" data-author-search="Chinnasamy, Harshini">Harshini Chinnasamy</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-Courtney-Erickson-Aff3" data-author-popup="auth-Courtney-Erickson-Aff3" data-author-search="Erickson, Courtney">Courtney Erickson</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-Ashley-Jacobs-Aff3" data-author-popup="auth-Ashley-Jacobs-Aff3" data-author-search="Jacobs, Ashley">Ashley Jacobs</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-Allison_K_-Duh-Aff4" data-author-popup="auth-Allison_K_-Duh-Aff4" data-author-search="Duh, Allison K.">Allison K. Duh</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-Ramya-Tunuguntla-Aff3" data-author-popup="auth-Ramya-Tunuguntla-Aff3" data-author-search="Tunuguntla, Ramya">Ramya Tunuguntla</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-Dorota_Danuta-Klysz-Aff3" data-author-popup="auth-Dorota_Danuta-Klysz-Aff3" data-author-search="Klysz, Dorota Danuta">Dorota Danuta Klysz</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-6733-6110"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-6733-6110</a></span><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 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-Carley-Fowler-Aff3" data-author-popup="auth-Carley-Fowler-Aff3" data-author-search="Fowler, Carley">Carley Fowler</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 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-Sean-Green-Aff2" data-author-popup="auth-Sean-Green-Aff2" data-author-search="Green, Sean">Sean Green</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 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-Barbara-Beebe-Aff3" data-author-popup="auth-Barbara-Beebe-Aff3" data-author-search="Beebe, Barbara">Barbara Beebe</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 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-Casey-Carr-Aff3" data-author-popup="auth-Casey-Carr-Aff3" data-author-search="Carr, Casey">Casey Carr</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 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-Michelle-Fujimoto-Aff3" data-author-popup="auth-Michelle-Fujimoto-Aff3" data-author-search="Fujimoto, Michelle">Michelle Fujimoto</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 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-Annie_Kathleen-Brown-Aff3" data-author-popup="auth-Annie_Kathleen-Brown-Aff3" data-author-search="Brown, Annie Kathleen">Annie Kathleen Brown</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 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-Ann_Louise_G_-Petersen-Aff3" data-author-popup="auth-Ann_Louise_G_-Petersen-Aff3" data-author-search="Petersen, Ann-Louise G.">Ann-Louise G. Petersen</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 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-Catherine-McIntyre-Aff8" data-author-popup="auth-Catherine-McIntyre-Aff8" data-author-search="McIntyre, Catherine">Catherine McIntyre</a><sup class="u-js-hide"><a href="#Aff8">8</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide 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-Aman-Siddiqui-Aff8" data-author-popup="auth-Aman-Siddiqui-Aff8" data-author-search="Siddiqui, Aman">Aman Siddiqui</a><sup class="u-js-hide"><a href="#Aff8">8</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide 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-Nadia-Lepori_Bui-Aff8" data-author-popup="auth-Nadia-Lepori_Bui-Aff8" data-author-search="Lepori-Bui, Nadia">Nadia Lepori-Bui</a><sup class="u-js-hide"><a href="#Aff8">8</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide 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-Katlin-Villar-Aff8" data-author-popup="auth-Katlin-Villar-Aff8" data-author-search="Villar, Katlin">Katlin Villar</a><sup class="u-js-hide"><a href="#Aff8">8</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide 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-Kymhuynh-Pham-Aff8" data-author-popup="auth-Kymhuynh-Pham-Aff8" data-author-search="Pham, Kymhuynh">Kymhuynh Pham</a><sup class="u-js-hide"><a href="#Aff8">8</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide 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-Rachel-Bove-Aff8" data-author-popup="auth-Rachel-Bove-Aff8" data-author-search="Bove, Rachel">Rachel Bove</a><sup class="u-js-hide"><a href="#Aff8">8</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide 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-Eric-Musa-Aff8" data-author-popup="auth-Eric-Musa-Aff8" data-author-search="Musa, Eric">Eric Musa</a><sup class="u-js-hide"><a href="#Aff8">8</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide 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-Warren_D_-Reynolds-Aff3" data-author-popup="auth-Warren_D_-Reynolds-Aff3" data-author-search="Reynolds, Warren D.">Warren D. Reynolds</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 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-Adam-Kuo-Aff3" data-author-popup="auth-Adam-Kuo-Aff3" data-author-search="Kuo, Adam">Adam Kuo</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 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-Snehit-Prabhu-Aff3" data-author-popup="auth-Snehit-Prabhu-Aff3" data-author-search="Prabhu, Snehit">Snehit Prabhu</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 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-Lindsey-Rasmussen-Aff9" data-author-popup="auth-Lindsey-Rasmussen-Aff9" data-author-search="Rasmussen, Lindsey">Lindsey Rasmussen</a><sup class="u-js-hide"><a href="#Aff9">9</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide 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-Timothy_T_-Cornell-Aff9" data-author-popup="auth-Timothy_T_-Cornell-Aff9" data-author-search="Cornell, Timothy T.">Timothy T. Cornell</a><sup class="u-js-hide"><a href="#Aff9">9</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide 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-Sonia-Partap-Aff1" data-author-popup="auth-Sonia-Partap-Aff1" data-author-search="Partap, Sonia">Sonia Partap</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 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-Paul_G_-Fisher-Aff1" data-author-popup="auth-Paul_G_-Fisher-Aff1" data-author-search="Fisher, Paul G.">Paul G. Fisher</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-1196-1590"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-1196-1590</a></span><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 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-Cynthia_J_-Campen-Aff1" data-author-popup="auth-Cynthia_J_-Campen-Aff1" data-author-search="Campen, Cynthia J.">Cynthia J. Campen</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-3519-1375"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-3519-1375</a></span><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 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-Gerald-Grant-Aff4" data-author-popup="auth-Gerald-Grant-Aff4" data-author-search="Grant, Gerald">Gerald Grant</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 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-Laura-Prolo-Aff4" data-author-popup="auth-Laura-Prolo-Aff4" data-author-search="Prolo, Laura">Laura Prolo</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 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-Xiaobu-Ye-Aff10" data-author-popup="auth-Xiaobu-Ye-Aff10" data-author-search="Ye, Xiaobu">Xiaobu Ye</a><sup class="u-js-hide"><a href="#Aff10">10</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide 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-Bita-Sahaf-Aff3" data-author-popup="auth-Bita-Sahaf-Aff3" data-author-search="Sahaf, Bita">Bita Sahaf</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 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-Kara_L_-Davis-Aff2-Aff3" data-author-popup="auth-Kara_L_-Davis-Aff2-Aff3" data-author-search="Davis, Kara L.">Kara L. Davis</a><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0002-7182-2592"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0002-7182-2592</a></span><sup class="u-js-hide"><a href="#Aff2">2</a>,<a href="#Aff3">3</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide 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-Steven_A_-Feldman-Aff3" data-author-popup="auth-Steven_A_-Feldman-Aff3" data-author-search="Feldman, Steven A.">Steven A. Feldman</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 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-Sneha-Ramakrishna-Aff2-Aff3" data-author-popup="auth-Sneha-Ramakrishna-Aff2-Aff3" data-author-search="Ramakrishna, Sneha" data-corresp-id="c2">Sneha Ramakrishna<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><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0001-7445-3190"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0001-7445-3190</a></span><sup class="u-js-hide"><a href="#Aff2">2</a>,<a href="#Aff3">3</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 54 authors for this article" title="Show all 54 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-Crystal-Mackall-Aff2-Aff3-Aff11-Aff12" data-author-popup="auth-Crystal-Mackall-Aff2-Aff3-Aff11-Aff12" data-author-search="Mackall, Crystal" data-corresp-id="c3">Crystal Mackall<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><span class="u-js-hide"> <a class="js-orcid" href="http://orcid.org/0000-0001-6323-4304"><span class="u-visually-hidden">ORCID: </span>orcid.org/0000-0001-6323-4304</a></span><sup class="u-js-hide"><a href="#Aff2">2</a>,<a href="#Aff3">3</a>,<a href="#Aff11">11</a>,<a href="#Aff12">12</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="/" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Nature</i></a> (<span data-test="article-publication-year">2024</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">24k <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">269 <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/s41586-024-08171-9/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/cancer-immunotherapy" data-track="click" data-track-action="view subject" data-track-label="link">Cancer immunotherapy</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> </ul> </div> </div> <div class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" 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">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><p>H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the disialoganglioside GD2 (ref. <sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Mount, C. W. et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M(+) diffuse midline gliomas. Nat. Med. 24, 572–579 (2018)." href="/articles/s41586-024-08171-9#ref-CR1" id="ref-link-section-d63664714e1100">1</a></sup>). Chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018)." href="/articles/s41586-024-08171-9#ref-CR2" id="ref-link-section-d63664714e1104">2</a></sup>. Arm A of Phase I trial no. <a href="https://clinicaltrials.gov/ct2/show/NCT03690193?term=NCT03690193">NCT04196413</a> (ref. <sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022)." href="/articles/s41586-024-08171-9#ref-CR3" id="ref-link-section-d63664714e1115">3</a></sup>) administered one intravenous (IV) dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal DMG (sDMG) at two dose levels (DL1, 1 × 10<sup>6</sup> kg<sup>−</sup><sup>1</sup>; DL2, 3 × 10<sup>6</sup> kg<sup>−1</sup>) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10–30 × 10<sup>6</sup> GD2-CART). Primary objectives were manufacturing feasibility, tolerability and the identification of maximally tolerated IV dose. Secondary objectives included preliminary assessments of benefit. Thirteen patients enroled, with 11 receiving IV GD2-CART on study (<i>n</i> = 3 DL1 (3 DIPG); <i>n</i> = 8 DL2 (6 DIPG, 2 sDMG)). GD2-CART manufacture was successful for all patients. No dose-limiting toxicities occurred on DL1, but three patients experienced dose-limiting cytokine release syndrome on DL2, establishing DL1 as the maximally tolerated IV dose. Nine patients received ICV infusions, with no dose-limiting toxicities. All patients exhibited tumour inflammation-associated neurotoxicity, safely managed with intensive monitoring and care. Four patients demonstrated major volumetric tumour reductions (52, 54, 91 and 100%), with a further three patients exhibiting smaller reductions. One patient exhibited a complete response ongoing for over 30 months since enrolment. Nine patients demonstrated neurological benefit, as measured by a protocol-directed clinical improvement score. Sequential IV, followed by ICV GD2-CART, induced tumour regressions and neurological improvements in patients with DIPG and those with sDMG.</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%2Fs41591-024-02875-1/MediaObjects/41591_2024_2875_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/s41591-024-02875-1?fromPaywallRec=false" data-track="select_recommendations_1" data-track-context="inline recommendations" data-track-action="click recommendations inline - 1" data-track-label="10.1038/s41591-024-02875-1">Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial </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">07 March 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%2Fs41591-024-02893-z/MediaObjects/41591_2024_2893_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/s41591-024-02893-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/s41591-024-02893-z">Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results </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">13 March 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%2Fs41591-021-01404-8/MediaObjects/41591_2021_1404_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/s41591-021-01404-8?fromPaywallRec=false" data-track="select_recommendations_3" data-track-context="inline recommendations" data-track-action="click recommendations inline - 3" data-track-label="10.1038/s41591-021-01404-8">Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis </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">12 July 2021</span> </div> </div> </article> </div> </div> </section> <script> window.dataLayer = window.dataLayer || []; window.dataLayer.push({ recommendations: { recommender: 'semantic', model: 'specter', policy_id: 'NA', timestamp: 1732332916, 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>Chimeric antigen receptors (CARs) couple an antigen-binding domain to T cell signalling domains to redirect T lymphocytes to cancer cells expressing a target of interest. Autologous CAR T cells have mediated impressive results in refractory B and plasma cell malignancies<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018)." href="#ref-CR2" id="ref-link-section-d63664714e1157">2</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017)." href="#ref-CR5" id="ref-link-section-d63664714e1157_1">5</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Nastoupil, L. J. et al. Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US Lymphoma CAR T Consortium. J. Clin. Oncol. 38, 3119–3128 (2020)." href="#ref-CR6" id="ref-link-section-d63664714e1157_2">6</a>,,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Schultz, L. M. et al. Disease burden affects outcomes in pediatric and young adult B-cell lymphoblastic leukemia after commercial tisagenlecleucel: a pediatric real-world chimeric antigen receptor consortium report. J. Clin. Oncol. 40, 945–955 (2022)." href="#ref-CR4" id="ref-link-section-d63664714e1160">4</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017)." href="#ref-CR5" id="ref-link-section-d63664714e1160_1">5</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Nastoupil, L. J. et al. Standard-of-care axicabtagene ciloleucel for relapsed or refractory large B-cell lymphoma: results from the US Lymphoma CAR T Consortium. J. Clin. Oncol. 38, 3119–3128 (2020)." href="#ref-CR6" id="ref-link-section-d63664714e1160_2">6</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Berdeja, J. G. et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet 398, 314–324 (2021)." href="/articles/s41586-024-08171-9#ref-CR7" id="ref-link-section-d63664714e1163">7</a></sup>, but have not demonstrated high rates of sustained antitumour effects in solid cancers or brain tumours<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Adusumilli, P. S. et al. A Phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab. Cancer Discov. 11, 2748–2763 (2021)." href="#ref-CR8" id="ref-link-section-d63664714e1167">8</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Ahmed, N. et al. HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: a Phase 1 dose-escalation trial. JAMA Oncol. 3, 1094–1101 (2017)." href="#ref-CR9" id="ref-link-section-d63664714e1167_1">9</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Ahmed, N. et al. Human epidermal growth factor receptor 2 (HER2) – specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J. Clin. Oncol. 33, 1688–1696 (2015)." href="#ref-CR10" id="ref-link-section-d63664714e1167_2">10</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Narayan, V. et al. PSMA-targeting TGFbeta-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat. Med. 28, 724–734 (2022)." href="#ref-CR11" id="ref-link-section-d63664714e1167_3">11</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Qi, C. et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial interim results. Nat. Med. 28, 1189–1198 (2022)." href="#ref-CR12" id="ref-link-section-d63664714e1167_4">12</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Brown, C. E. et al. Locoregional delivery of IL-13Ralpha2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial. Nat. Med. 30, 1001–1012 (2024)." href="#ref-CR13" id="ref-link-section-d63664714e1167_5">13</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Choi, B. D. et al. Intraventricular CARv3-TEAM-E T cells in recurrent glioblastoma. N. Engl. J. Med. 390, 1290–1298 (2024)." href="#ref-CR14" id="ref-link-section-d63664714e1167_6">14</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="Bagley, S. J. et al. Repeated peripheral infusions of anti-EGFRvIII CAR T cells in combination with pembrolizumab show no efficacy in glioblastoma: a phase 1 trial. Nat. Cancer 5, 517–531 (2024)." href="/articles/s41586-024-08171-9#ref-CR15" id="ref-link-section-d63664714e1170">15</a></sup>, with the exception of promising responses in a recent trial of GD2-CAR T cell therapy for neuroblastoma<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Del Bufalo, F. et al. GD2-CART01 for relapsed or refractory high-risk neuroblastoma. N. Engl. J. Med. 388, 1284–1295 (2023)." href="/articles/s41586-024-08171-9#ref-CR16" id="ref-link-section-d63664714e1174">16</a></sup>. Differential rates of activity between liquid cancers and solid/brain tumours may relate to a dearth of safe targets with high homogenous expression, inadequate T cell trafficking and/or T cell dysfunction induced by the tumour microenvironment.</p><p>H3K27M-mutated diffuse midline gliomas (DMGs) chiefly occur in children and young adults and originate in midline structures of the nervous system. Patients with pontine DMG (also called diffuse intrinsic pontine glioma, DIPG) have a median overall survival of 11 months from diagnosis, and 5 year overall survival below 1% (refs. <sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Cooney, T. et al. Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study. Neuro Oncol. 19, 1279–1280 (2017)." href="#ref-CR17" id="ref-link-section-d63664714e1181">17</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Mackay, A. et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 32, 520–537 (2017)." href="#ref-CR18" id="ref-link-section-d63664714e1181_1">18</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Baxter, P. A. et al. A phase I/II study of veliparib (ABT-888) with radiation and temozolomide in newly diagnosed diffuse pontine glioma: a Pediatric Brain Tumor Consortium study. Neuro Oncol. 22, 875–885 (2020)." href="/articles/s41586-024-08171-9#ref-CR19" id="ref-link-section-d63664714e1184">19</a></sup>). Patients with DMGs outside of the brainstem, including the spinal cord, have a median overall survival of 13 months<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Mackay, A. et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 32, 520–537 (2017)." href="/articles/s41586-024-08171-9#ref-CR18" id="ref-link-section-d63664714e1188">18</a></sup>. DIPG is the most common cause of death due to brain cancer in children, with palliative radiotherapy the standard of care. Cytotoxic chemotherapy has not improved outcomes to date<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Robison, N. J. & Kieran, M. W. Diffuse intrinsic pontine glioma: a reassessment. J. Neurooncol. 119, 7–15 (2014)." href="/articles/s41586-024-08171-9#ref-CR20" id="ref-link-section-d63664714e1192">20</a></sup>. Although targeted therapies and immuno-oncology strategies have begun to show early promise<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Venneti, S. et al. Clinical efficacy of ONC201 in H3K27M-mutant diffuse midline gliomas is driven by disruption of integrated metabolic and epigenetic pathways. Cancer Discov. 13, 2370–2393 (2023)." href="#ref-CR21" id="ref-link-section-d63664714e1196">21</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Gallego Perez-Larraya, J. et al. Oncolytic DNX-2401 virus for pediatric diffuse intrinsic pontine glioma. N. Engl. J. Med. 386, 2471–2481 (2022)." href="#ref-CR22" id="ref-link-section-d63664714e1196_1">22</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Grassl, N. et al. A H3K27M-targeted vaccine in adults with diffuse midline glioma. Nat. Med. 29, 2586–2592 (2023)." href="/articles/s41586-024-08171-9#ref-CR23" id="ref-link-section-d63664714e1199">23</a></sup>, outcomes remain dismal.</p><p>We discovered high, uniform expression of GD2, a disialoganglioside, on H3K27M<sup>+</sup> DMG cells and demonstrated that intravenous (IV) administration of chimeric antigen receptor-modified T cells targeting GD2 (GD2-CART) eradicated established DMGs in patient-derived orthotopic xenograft mouse models<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Mount, C. W. et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M(+) diffuse midline gliomas. Nat. Med. 24, 572–579 (2018)." href="/articles/s41586-024-08171-9#ref-CR1" id="ref-link-section-d63664714e1208">1</a></sup>. We and others also demonstrated increased potency and decreased systemic inflammation following intracerebroventricular (ICV) administration of CAR T cells compared with IV administration in preclinical brain tumour models<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Theruvath, J. et al. Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors. Nat. Med. 26, 712–719 (2020)." href="#ref-CR24" id="ref-link-section-d63664714e1212">24</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Wang, X. et al. The cerebroventricular environment modifies CAR T cells for potent activity against both central nervous system and systemic lymphoma. Cancer Immunol. Res. 9, 75–88 (2021)." href="#ref-CR25" id="ref-link-section-d63664714e1212_1">25</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Priceman, S. J. et al. Regional delivery of chimeric antigen receptor-engineered T cells effectively targets HER2(+) breast cancer metastasis to the brain. Clin. Cancer Res. 24, 95–105 (2018)." href="#ref-CR26" id="ref-link-section-d63664714e1212_2">26</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Donovan, L. K. et al. Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma. Nat. Med. 26, 720–731 (2020)." href="/articles/s41586-024-08171-9#ref-CR27" id="ref-link-section-d63664714e1215">27</a></sup>. These data provided rationale for this first-in-human/first-in-child phase 1 clinical trial (<a href="https://clinicaltrials.gov/ct2/show/NCT04196413">NCT04196413</a>, a phase 1 clinical trial of autologous GD2-CART for DIPG and spinal diffuse midline glioma (sDMG)). We previously reported antitumour activity and correlative findings from the first three patients treated on <a href="https://clinicaltrials.gov/ct2/show/NCT04196413">NCT04196413</a> arm A at dose level 1 (DL1), and a fourth who enroled on trial but received therapy through a single-patient-compassionate investigational new drug (IND) application <sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022)." href="/articles/s41586-024-08171-9#ref-CR3" id="ref-link-section-d63664714e1234">3</a></sup>. Here we report final clinical results following enrolment completion of arm A, which demonstrate the tolerability of 1 × 10<sup>6</sup> GD2-CART cells per kg administered intravenously (DL1) followed by sequential ICV infusions, tumour regressions and, in some cases, sustained antitumour effects in patients with DIPG and sDMG.</p></div></div></section><section data-title="Trial design"><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">Trial design</h2><div class="c-article-section__content" id="Sec2-content"><p>Eligible patients were 2–30 years of age, with biopsy-confirmed H3K27M-mutated DIPG or sDMG, who had completed standard frontline radiotherapy at least 4 weeks before enrolment, were not receiving corticosteroid therapy and had acceptable performance status (Lansky or Karnofsky score 60 or above). Although patients typically exhibited bulky disease in the brainstem or spinal cord, those with bulky disease involving the thalamus or cerebellum were not eligible due to increased risk of toxicity of GD2-CART observed with these tumour locations in murine models<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Mount, C. W. et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M(+) diffuse midline gliomas. Nat. Med. 24, 572–579 (2018)." href="/articles/s41586-024-08171-9#ref-CR1" id="ref-link-section-d63664714e1248">1</a></sup>. Patients with clinically significant dysphagia (as an indicator of significant medullary dysfunction) were also ineligible. Detailed eligibility and exclusion criteria are given in Supplementary Methods <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">1</a>. The clinical trial protocol was approved by the Stanford Institutional Review Board and registered with ClinicalTrials.gov (<a href="https://clinicaltrials.gov/ct2/show/NCT04196413">NCT04196413</a>). Informed patient or parent consent and child assent were obtained.</p><p>Primary objectives were the determination of the feasibility of manufacturing, assessment of safety and tolerability and identification of a maximally tolerated and/or recommended Phase 2 dose of IV GD2-CART following lymphodepleting chemotherapy in this population. Secondary objectives (detailed in Supplementary Methods <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">2</a>, section <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">1</a>) included preliminary assessment of benefit as measured by radiographic response on magnetic resonance imaging (MRI) and by clinical improvement in neurological dysfunction. IV doses were escalated using a 3 + 3 design, based on the occurrence of dose-limiting toxicities (DLTs) possibly, probably or most likely attributed to IV GD2-CAR T and occurring within 28 days following infusion. DLTs comprised any grade 5 toxicity, grade 4 cytokine release syndrome (CRS), grade 4 neurotoxicity lasting at least 96 h, new grade 3 neurotoxicity lasting at least 28 days, grade 4 neutropenia or thrombocytopenia lasting more than 28 days and grade 3 or greater non-haematologic toxicity, with the exceptions of those detailed in Supplementary Methods <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">2</a>, section <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">5.4.5</a>. Because sDMGs are rare, the protocol allowed safety in the DIPG cohort to inform dose escalation for patients with sDMG but, given the risk for neurotoxicity related to the location of DIPG, safety in sDMG patients did not inform dose escalation for patients with DIPG.</p><p>In December 2020, a protocol amendment added a new secondary objective to evaluate safety and assess clinical benefit to patients treated with IV GD2-CAR T cells followed by ICV administration of GD2-CAR T cells (Supplementary Methods <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">2</a>). Patients were eligible to receive second or subsequent IV or ICV infusions if they showed complete response, partial response, minor response or stable disease radiographically on MRI, or had evidence for clinical benefit from preinfusion baseline according to the protocol-specified clinical neurological examination, and if at least 28 days had elapsed since the initial GD2-CART infusion or 21 days from subsequent infusions, circulating CAR T cell levels were below 5% and toxicity had resolved to below grade 2. Lymphodepletion was not administered before ICV infusions. All subsequent infusions were delivered intracerebroventricularly.</p><p>Following enrolment on the trial, no additional, non-protocol-directed chemotherapies, molecularly targeted therapies or immunotherapies were allowed. Local therapies such as intratumoural cyst drainage or re-irradiation were allowed; if re-irradiation was administered, subsequent infusions resumed after 4 weeks from the end of re-irradiation.</p></div></div></section><section data-title="GD2-CART manufacture"><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">GD2-CART manufacture</h2><div class="c-article-section__content" id="Sec3-content"><p>GD2-CART were manufactured in the automated CliniMACS Prodigy with IL-7 (Miltenyi Biotec, 12.5 ng ml<sup>−1</sup>) and IL-15 (Miltenyi Biotec, 12.5 ng ml<sup>−1</sup>) in the presence of dasatinib (Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig4">1a</a> and Supplementary Methods <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">3</a>), and cryopreserved at day 7 of culture. The GD2-CAR was encoded by a retroviral vector encoding an iCasp9 domain (Bellicum Pharmaceuticals, Inc.), and GD2.4-1BB.CD3z CAR separated by a P2A ribosomal skip sequence (Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig4">1b</a>).</p></div></div></section><section data-title="Toxicity monitoring and management"><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">Toxicity monitoring and management</h2><div class="c-article-section__content" id="Sec4-content"><p>Patients received standard supportive care for seizure prophylaxis, immunosuppression associated with lymphodepleting chemotherapy, CRS and immune effector cell acute neurotoxicity syndrome (ICANS), as detailed in Supplementary Methods <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">4</a>. Neurotoxicity that was distinct from ICANS and attributable to local tumour inflammation was designated tumour inflammation-associated neurotoxicity (TIAN)<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Theruvath, J. et al. Locoregionally administered B7-H3-targeted CAR T cells for treatment of atypical teratoid/rhabdoid tumors. Nat. Med. 26, 712–719 (2020)." href="/articles/s41586-024-08171-9#ref-CR24" id="ref-link-section-d63664714e1318">24</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Mahdi, J. et al. Tumor inflammation-associated neurotoxicity. Nat. Med. 29, 803–810 (2023)." href="/articles/s41586-024-08171-9#ref-CR28" id="ref-link-section-d63664714e1321">28</a></sup> and graded using NCI Common Terminology Criteria for Adverse Events v.5.0. For mitigation of risks associated with TIAN, we implemented a toxicity-monitoring and toxicity-management algorithm that (1) placed Ommaya catheters or similar devices for intracranial pressure monitoring and potential treatment of hydrocephalus in all patients; (2) incorporated sequential neurological examinations and scheduled and symptom-prompted intracerebral pressure monitoring; (3) prescribed measures to lower elevated intracranial pressure (positioning, hypertonic saline (3%), cerebrospinal fluid (CSF) removal) in patients with documented elevated intracranial pressure; and (4) administered anakinra and corticosteroids to patients with significant neurological symptoms (detailed in Supplementary Methods <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">4</a>).</p></div></div></section><section data-title="Demographics"><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">Demographics</h2><div class="c-article-section__content" id="Sec5-content"><p>Enrolment began in June 2020 and the data cut-off was 1 December 2023. A consort diagram is shown in Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig5">2</a>. Characteristics of the 13 enroled patients are shown in Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41586-024-08171-9#Tab1">1</a>. Median age was 15 years (range 4–30 years), and seven patients were female; ten patients had DIPG and three had sDMG. The H3K27M mutation was demonstrated in biopsies from all tumours by either immunohistochemistry or DNA sequencing. Median time from diagnosis to enrolment was 5.0 months (range 3.9–11.6 months). Eight patients had disease progression or pseudoprogression on MRI imaging at enrolment, and five did not have documented progression at enrolment. Two patients (nos. 002 and 011) were removed from the study before treatment due to rapid tumour progression and a decline in performance status rendering them ineligible for protocol-directed therapy. Patient no. 002 was treated on a single-patient-compassionate IND, with outcomes for this patient reported previously<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022)." href="/articles/s41586-024-08171-9#ref-CR3" id="ref-link-section-d63664714e1342">3</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 Patient demographics and GD2-CAR T cell infusions received</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/s41586-024-08171-9/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></div></section><section data-title="Cell manufacture and characterization"><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">Cell manufacture and characterization</h2><div class="c-article-section__content" id="Sec6-content"><p>For the 13 enroled patients, 20 GD2-CART products were successfully manufactured (Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig4">1</a>), including seven CAR T cell products remanufactured to support multiple repeated ICV infusions. The product for patient no. 011 was not characterized, because this patient developed rapid tumour progression and died before CAR T cell infusion. Mean manufacturing duration was 7 days. The median time from enrolment to IV GD2-CART infusion was 22.9 days (range 15–38 days). Product functional assessment demonstrated GD2-specific reactivity (Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig6">3a,b</a>). Products demonstrated a mean fold T cell expansion of 21.97 (range 12.16–28.06), mean percentage viability of 93.51 (range 86.8–96.9), mean transduction efficiency of 57.27 (range 21.63–83.80) (Supplementary Table <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">1</a>) and mean vector copy number per CAR<sup>+</sup> cell of 3.17 (range 0.84–7.20) (Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig6">3c,d</a>). Detailed GD2-CART phenotypic composition of 19 products showed a predominance of central memory T cells (Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig4">1c–f</a>).</p></div></div></section><section data-title="Treatment received and toxicity"><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">Treatment received and toxicity</h2><div class="c-article-section__content" id="Sec7-content"><p>Of 11 patients who received one IV GD2-CART infusion on study, 9 experienced clinical benefit, imaging benefit on MRI or both and received additional ICV infusions, as noted in Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41586-024-08171-9#Tab1">1</a> (median of four infusions, range 1–17), administered over 1.0–29.4 months at the time of data cut-off. Incidence and grade of CRS, ICANS and TIAN following each IV and ICV infusion are shown in Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig1">1a</a>, Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41586-024-08171-9#Tab2">2</a> and Supplementary Tables <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">2</a> and <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">3</a>. Following IV GD2-CART, all patients experienced CRS, with one of three patients on DL1 experiencing grade 2 CRS, six of eight patients on DL2 experiencing grade 2 or higher CRS and three patients on DL2 experiencing DLT attributed to grade 4 CRS (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41586-024-08171-9#Tab2">2</a>). CRS was similar in nature to that observed in other CAR T cell trials<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Del Bufalo, F. et al. GD2-CART01 for relapsed or refractory high-risk neuroblastoma. N. Engl. J. Med. 388, 1284–1295 (2023)." href="/articles/s41586-024-08171-9#ref-CR16" id="ref-link-section-d63664714e2207">16</a></sup>. The three instances of grade 4 CRS were characterized by hypotension requiring multiple pressors (one patient), pulmonary oedema and respiratory failure requiring either bilevel positive airway pressure/continuous positive airway pressure (one patient) or intubation (one patient). CRS was managed according to established guidelines using tocilizumab, anakinra, corticosteroids (dexamethasone and methylprednisolone), fluid resuscitation and supportive care. Following IV GD2-CART, we observed ICANS in one of three patients at DL1 (grade 2) and in four of eight patients at DL2 (<i>n</i> = 1 grade 3, <i>n</i> = 3 grade 1). Based on these results, we identified DL2 (3 × 10<sup>6 </sup>GD2-CART per kg) as exceeding the maximally tolerated dose for IV administration in patients with DIPG/DMG.</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="Toxicity and response measures."><figure><figcaption><b id="Fig1" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 1: Toxicity and response measures.</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/s41586-024-08171-9/figures/1" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig1_HTML.png?as=webp"><img aria-describedby="Fig1" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig1_HTML.png" alt="figure 1" loading="lazy" width="685" height="584"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-1-desc"><p><b>a</b>, Number of patients experiencing CRS (left), ICANS (middle) and TIAN (right) following each infusion. Grade of maximal toxicity is indicated by colour in legend. Infusion no. 1 was administered intravenously, infusions 2–17 intracerebroventricularly. <b>b</b>, Left, waterfall plot depicting best volumetric change in tumour volume following GD2-CART therapy from baseline measured prior to the first infusion. Asterisks (*) indicate those patients with documented disease progression at the time of first GD2-CAR T cell infusion. The time point at which best radiographic change was measured is noted above the waterfall plot for each patient. Black, patients with DIPG treated at DL1 (<i>n</i> = 3 patients); white, patients with DIPG treated at DL2 (<i>n</i> = 8 patients); hatched markings, patients with sDMG treated at DL2. Right, violin plot of best volumetric change in tumour volume from baseline, illustrating the normal (Gaussian) distribution of responses; see also Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig7">4a</a> for Q–Q plot demonstrating normal distribution of these data. Each point represents one patient (<i>n</i> = 11 patients). <b>c</b>, Swimmer plot depicting patient survival. Each bar represents the time from diagnosis to first treatment (yellow), time on trial (blue), time until death (red dot) or data cut-off for individual patients (<i>n</i> = 11 patients). Patients remained on trial (blue) until disease progression that was unresponsive to CAR T cell therapy; time elapsing between removal from study for disease progression and death is depicted in grey. Vertical marks indicate each ICV infusion, asterisks indicate time of trial enrolment; first treatment indicated on the <i>y</i> axis at time 0. Pause in infusions for focal therapy was allowed per protocol, and three patients (nos. 006, 007 and 009) received re-irradiation, as indicated by orange diamonds. Imaging and clinical benefit in patient nos. 003 and 004 were previously reported<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Schultz, L. M. et al. Disease burden affects outcomes in pediatric and young adult B-cell lymphoblastic leukemia after commercial tisagenlecleucel: a pediatric real-world chimeric antigen receptor consortium report. J. Clin. Oncol. 40, 945–955 (2022)." href="/articles/s41586-024-08171-9#ref-CR4" id="ref-link-section-d63664714e2258">4</a></sup>; note that, in the previous report<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Schultz, L. M. et al. Disease burden affects outcomes in pediatric and young adult B-cell lymphoblastic leukemia after commercial tisagenlecleucel: a pediatric real-world chimeric antigen receptor consortium report. J. Clin. Oncol. 40, 945–955 (2022)." href="/articles/s41586-024-08171-9#ref-CR4" id="ref-link-section-d63664714e2262">4</a></sup>, our patient no. 001 was described as DIPG Patient 1, patient no. 003 as DIPG Patient 2 and patient no. 004 as DIPG Patient 3.</p><p><a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM4">Source Data</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/s41586-024-08171-9/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><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 Maximum toxicity grades following GD2-CAR T therapy</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/s41586-024-08171-9/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>Among 62 ICV infusions, no DLTs occurred. Forty-one ICV infusions (66%) were associated with no CRS. Among 19 ICV infusions associated with CRS, most were low grade (<i>n</i> = 16 grade 1; <i>n</i> = 4 infusions in two patients grade 2; <i>n</i> = 1 grade 3 in the context of urosepsis in a patient with sDMG) (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41586-024-08171-9#Tab2">2</a>). No ICANS was observed following ICV infusions. One patient (no. 005) experienced a grade 3 sensory neuropathy (Supplementary Table <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">4</a>) in a stocking-glove distribution following the first infusion, for which vitamin B<sub>6</sub> toxicity was considered a contributory factor; this resolved following vitamin B<sub>6</sub> supplement cessation. Of note, we did not observe any cases of transient painful peripheral neuropathy commonly associated with anti-GD2 antibody therapy<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Yu, A. L. et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N. Engl. J. Med. 363, 1324–1334 (2010)." href="/articles/s41586-024-08171-9#ref-CR29" id="ref-link-section-d63664714e2788">29</a></sup>. As previously reported<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022)." href="/articles/s41586-024-08171-9#ref-CR3" id="ref-link-section-d63664714e2792">3</a></sup>, one patient (no. 003) experienced a grade 5 intratumoural haemorrhage (Supplementary Table <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">4</a>) in a region of known intratumoural vascular anomaly. Intratumoural haemorrhages occur relatively frequently in DIPG; risk increases with time from diagnosis, and symptomatic intratumoural haemorrhages occur in around 20% of patients with DIPG by 12 months from diagnosis<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Broniscer, A. et al. Intratumoral hemorrhage among children with newly diagnosed, diffuse brainstem glioma. Cancer 106, 1364–1371 (2006)." href="/articles/s41586-024-08171-9#ref-CR30" id="ref-link-section-d63664714e2799">30</a></sup>.</p><p>We observed TIAN in 91% of patients following IV infusion and in 100% of patients following the first ICV infusion; TIAN grade typically diminished with subsequent infusions (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig1">1a</a>). Forty-four ICV infusions (71%) were associated with TIAN. Nine of nine (100%) patients with DIPG developed TIAN following IV GD2-CART (<i>n</i> = 2 grade 4, <i>n</i> = 3 grade 3 and <i>n</i> = 4 grade 2), and 67% of patients with DIPG developed TIAN following ICV GD2-CAR T cell infusions (<i>n</i> = 29 of 43 infusions with TIAN: grade 4, <i>n</i> = 1; grade 3, <i>n</i> = 3; grade 2, <i>n</i> = 9; grade 1, <i>n</i> = 16). TIAN reversed in all patients following treatment according to our toxicity management algorithm, and no patient experienced a DLT due to TIAN. In one patient with sDMG, high-grade communicating hydrocephalus was observed during peak tumour inflammation. The agent available for ablation of CAR T cells by the induction of caspase-9, AP1903, was not administered to any patients treated on arm A.</p></div></div></section><section data-title="Response"><div class="c-article-section" id="Sec8-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec8">Response</h2><div class="c-article-section__content" id="Sec8-content"><p>Experience with the first three patients enroled suggested a hypothesized risk of progression approximately 2–3 months following IV infusion<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022)." href="/articles/s41586-024-08171-9#ref-CR3" id="ref-link-section-d63664714e2842">3</a></sup>, including patient no. 003, who showed an impressive response to IV infusion, followed by progression at approximately day 70, with response to subsequent ICV infusion. Based on this experience, beginning with patient no. 004, the protocol was amended to allow patients with clinical or imaging benefit following IV infusion to receive multiple sequential ICV infusions. Patients were eligible to receive ICV infusions every 1–3 months, providing they had experienced stable disease or clinical or imaging benefit with the previous infusion.</p><p>Several patients exhibited reduction in tumour size following GD2-CART, with the best volumetric change in tumour size for each patient shown in Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig1">1b</a>. In this patient cohort, this ‘best response’ change in tumour volume data fits a Gaussian distribution by the Shapiro–Wilk test of normality, with no outliers (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig1">1b</a> and Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig7">4a</a>). Overall survival from time of diagnosis to trial enrolment, and from first GD2-CART administration to time off trial, death or data cut-off, is shown in Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig1">1c</a>. Patient no. 010 (DIPG), who was enroled with evidence of progression or possible pseudoprogression by imaging following completion of upfront radiotherapy, demonstrated a continuing reduction in tumour volume to the point of complete response within months following the first GD2-CAR T cell infusion. This complete response was sustained at 30 months following enrolment, the time of data cut-off, and is ongoing (Figs. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig1">1b</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig2">2a,b</a>). Patient no. 006 (sDMG), who was in clear clinical and radiographic tumour progression at the time of first treatment, demonstrated 91% reduction in tumour volume by 7 months following the first GD2-CAR T cell infusion (Figs. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig1">1b</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig3">3a,b</a>). Changes in tumour volume over time for additional patients are shown in Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig7">4b</a>.</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="Therapeutic response and correlative findings for patient no. 010."><figure><figcaption><b id="Fig2" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 2: Therapeutic response and correlative findings for patient no. 010.</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/s41586-024-08171-9/figures/2" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig2_HTML.png?as=webp"><img aria-describedby="Fig2" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig2_HTML.png" alt="figure 2" loading="lazy" width="685" height="506"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-2-desc"><p><b>a</b>, T2-weighted, axial MRI images of tumour at midbrain, pons and medulla levels at baseline and at 3, 5, 16 and 29 months following first infusion. Red arrowheads indicate T2 signal abnormality. At baseline, extensive tumour involving the midbrain (left more than right), pons and medulla is evident, with mass obscuring the fourth ventricle at baseline resolving by 3 months. At 3 months, return of CSF around the brainstem is evident as the size of the brainstem normalizes, and T2 signal normalizes throughout much of the brainstem. At 3 months, T2 signal abnormality, probably represening tumour, remains around the area of the biopsy tract in the pons (red arrowhead) and resolves by 5 months. At 5, 16 and 29 months, the arrowheads indicate stable T2 signal abnormality of the biopsy tract and stable area of subtle T2 hyperintensity of unclear significance in the medulla (as standard for axial MRI images, the patient’s left is the reader’s right). <b>b</b>, Tumour volume as a function of days following first GD2-CAR T infusion. <b>c</b>, Overlay of clinical change, CAR T cell persistence and tumour cell-free DNA. Clinical improvement is depicted as a bar at the top of the panel: red, clinical worsening from baseline; green, clinical improvement from baseline. CAR T cell persistence in blood, as measured by CAR construct quantitative PCR (qPCR, blue data points, left <i>y</i> axis). Cell-free tumour DNA (H3K27M) in CSF by digital droplet PCR (ddPCR, red data points, right <i>y</i> axis). GD2-CART infusions indicated as dotted vertical lines. Each qPCR data point represents the mean of three technical replicates; each ddPCR data point represents the mean of four technical replicates; error bars represent s.e.m. <b>d</b>, CSF cytokine levels following each infusion, expressed as log<sub>2</sub> fold change (FC) from day 0 before the first infusion. Time points are days from first infusion (first infusion administered intravenously, subsequent infusions administered intracerebroventricularly); infusions are separated by vertical white spacing; infusion number indicated by coloured bar above each heatmap; each square of the heat map represents one biological replicate. LLOQ, lower level of quantitation.</p><p><a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM4">Source Data</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/s41586-024-08171-9/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><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-3" data-title="Therapeutic response and correlative findings for patient no. 006."><figure><figcaption><b id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 3: Therapeutic response and correlative findings for patient no. 006.</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/s41586-024-08171-9/figures/3" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig3_HTML.png?as=webp"><img aria-describedby="Fig3" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig3_HTML.png" alt="figure 3" loading="lazy" width="685" height="544"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-3-desc"><p><b>a</b>, T2-weighted, sagittal (left) and axial (right) MRI images of spinal cord DMG at baseline and at 2, 6 and 9 months following first infusion. Red outline indicates T2 signal abnormality (tumour). At baseline, tumour centred at T11/12 spinal level diffusely involves the spinal cord and expands the cord to fill the entire spinal canal, with no CSF visualized around cord. Tumour infiltration of the cord progressively improves until it is of normal calibre and T2 signal abnormality is minimal (red arrow). <b>b</b>, Tumour volume as a function of time (days) following first GD2-CART infusion. <b>c</b>, Overlay of clinical change, CAR T cell persistence and tumour cell-free DNA. Clinical improvement is depicted as a bar at the top of the panel, with solid green indicating clinical improvement from baseline and hatched green indicating improvement from pretreatment baseline but worsened from peak improvement. CAR T cell persistence in blood, as measured by qPCR of the CAR construct, is denoted by blue circles (left <i>y</i> axis); cell-free tumour DNA (H3K27M) in CSF, as measured by ddPCR, is indicated by red squares (right <i>y</i> axis). Each qPCR data point represents the mean of three technical replicates; each ddPCR data point represents the mean of four technical replicates; error bars represent s.e.m. GD2-CART infusions indicated as dotted vertical lines. Note that, as CAR T cells become undetectable in blood by qPCR, cell-free tumour DNA elevates; this inflection point correlates with the beginning of disease progression. <b>d</b>, CSF cytokine levels following each infusion, expressed as log<sub>2</sub> fold change from day 0 before the first infusion. Time points represent days from first infusion (first infusion administered intravenously, subsequent infusions administered intracerebroventricularly); infusions separated by vertical white spacing; infusion number indicated by coloured bar above each heatmap; each square of the heatmap represents one biological replicate.</p><p><a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM4">Source Data</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/s41586-024-08171-9/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>Clinical improvements, as measured by changes in clinical improvement score (CIS), were also observed (Supplementary Table <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">5</a> and Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig12">9</a>). In general, clinical improvement coincided with tumour response on MRI (Figs. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig2">2c</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig3">3c</a>). For example, before the first infusion, patient no. 006 (sDMG) had severe paraplegia, neuropathic pain and bowel and bladder dysfunction. At the time of her best overall response (over 90% tumour reduction), she experienced intact bowel and bladder continence, markedly improved pain, and improved lower extremity function enabling ambulation with a cane. Similarly, patient no. 010 (DIPG) had sensory and motor deficits requiring assistance with gait at enrolment (used a wheelchair for longer distances) and experienced a complete response by imaging accompanied by significant clinical improvements, including improved left-sided hearing, improved hemifacial, hemibody and taste sensation, improved motor coordination and improved gait to the point of independent ambulation. For some patients, however, the relationship between imaging findings on MRI and clinical improvement was not direct, with patients no. 004 and no. 007 demonstrating sustained clinical improvement without substantial changes in overall tumour volume by MRI, and patient no. 012 exhibiting early clinical improvement but overall increase in tumour volume (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig1">1b</a>, Extended Data Figs. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig7">4b</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig12">9</a> and Supplementary Table <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">5</a>).</p><p>Median overall survival for patients treated on arm A was 20.6 months from diagnosis, with two patients with DIPG alive and followed subsequent to data cut-off (patient no. 007, length of follow-up 33 months; and patient no. 010, length of follow-up 30 months). For patients with DIPG, median overall survival was 17.6 months and for sDMG was 31.96 months (Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig7">4c</a>); comparison with historical controls was not possible in this study due to the highly selected nature of the trial cohort.</p></div></div></section><section data-title="Correlative findings"><div class="c-article-section" id="Sec9-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec9">Correlative findings</h2><div class="c-article-section__content" id="Sec9-content"><p>Peripheral blood demonstrated GD2-CART expansion following IV infusion at levels similar to those seen in other active CAR T cell trials<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014)." href="#ref-CR31" id="ref-link-section-d63664714e3007">31</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Lee, D. W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528 (2015)." href="#ref-CR32" id="ref-link-section-d63664714e3007_1">32</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Fry, T. J. et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat. Med. 24, 20–28 (2018)." href="/articles/s41586-024-08171-9#ref-CR33" id="ref-link-section-d63664714e3010">33</a></sup>, which persisted during ICV infusions (Figs. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig2">2c</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig3">3c</a> and Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig8">5a</a>) but decreased over time. GD2-CART expansion was also evident in CSF following multiple repeated infusions (Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig8">5b</a>). Patient nos. 006 (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig3">3c</a>) and 009 (Extended Data Figs. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig7">4a</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig8">5a</a>) experienced loss of detectable GD2-CART in the peripheral blood, as measured by PCR, temporally correlated with clinical and/or imaging progression. Increased cytokine/chemokine levels were present in peripheral blood following IV GD2-CART, whereas cytokine/chemokine levels were more marked in CSF following ICV GD2-CART (Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig9">6</a>), consistent with our previous report of DL1 patients<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022)." href="/articles/s41586-024-08171-9#ref-CR3" id="ref-link-section-d63664714e3039">3</a></sup>. Sequential ICV GD2-CART infusions induced repeated, transient elevations in CSF cytokine/chemokine levels (Figs. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig2">2d</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig3">3d</a> and Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig9">6</a>).</p><p>Grade 2 and greater CRS correlated with increased plasma levels of the myeloid cell chemokine MCP1 (also called CCL2), and a trend towards increased levels of the T cell cytokine IL-2 following IV GD2-CART administration (Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig10">7a</a>). Grade 2 and greater TIAN correlated with increased CSF levels of IL-10 and MCP1, and a trend towards increased levels of TNF following ICV GD2-CART (Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig10">7b</a>). For examination of the correlates of response, we assigned patients to ‘responder’ and ‘non-responder’ groups based on their best tumour volume changes (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig1">1b</a>), with three patients defined as non-responders (overall increase in tumour size) and eight defined as responders (decrease in tumour size or overall stable tumour size and improvement in neurological function). Using this stratification, we found no differences in the CD4:CD8 ratio of the CAR T cell product between responders and non-responders (Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig10">7c</a>), but responders exhibited higher levels of IL-2 in plasma following IV GD2-CART administration (Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig10">7d</a>), potentially reflecting increased T cell activation in these patients. In individual patients, progression was temporally associated with a decrease in plasma IP-10 or CXCL10 (Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig10">7e</a>). CSF levels of immunosuppressive TGF-beta factors increased following GD2-CART administrations in some patients, and higher TGF-beta1 levels early following GD2-CART infusion trended with progression of disease (Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig11">8a–c</a>). Notably, TGF-beta levels in CSF were relatively low in patient no. 010, who had a complete response, throughout his course (Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig11">8a,b</a>).</p><p>Cell-free tumour DNA (ctDNA) in CSF, as measured by ddPCR, demonstrated decreased H3K27M mutations per millilitre CSF in some patients associated with tumour regression, and increased levels at times of peak inflammation or when patients experienced clinical and/or imaging progression (Figs. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig2">2c</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig3">3c</a> and Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig8">5a</a>). Taken together, these data demonstrate evidence for sustained expansion and persistence of GD2-CART in the blood of patients with DIPG and sDMG, associated with clinical and biological evidence of antitumour activity, and begin to identify potential contributors to, or correlates of, loss of durable response in patients.</p></div></div></section><section data-title="Discussion"><div class="c-article-section" id="Sec10-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec10">Discussion</h2><div class="c-article-section__content" id="Sec10-content"><p>Recent advances in fundamental understanding of DMG have begun to translate to clinical advances<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Venneti, S. et al. Clinical efficacy of ONC201 in H3K27M-mutant diffuse midline gliomas is driven by disruption of integrated metabolic and epigenetic pathways. Cancer Discov. 13, 2370–2393 (2023)." href="#ref-CR21" id="ref-link-section-d63664714e3101">21</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Gallego Perez-Larraya, J. et al. Oncolytic DNX-2401 virus for pediatric diffuse intrinsic pontine glioma. N. Engl. J. Med. 386, 2471–2481 (2022)." href="#ref-CR22" id="ref-link-section-d63664714e3101_1">22</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Grassl, N. et al. A H3K27M-targeted vaccine in adults with diffuse midline glioma. Nat. Med. 29, 2586–2592 (2023)." href="/articles/s41586-024-08171-9#ref-CR23" id="ref-link-section-d63664714e3104">23</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Mueller, S. et al. PNOC015: repeated convection enhanced delivery (CED) of MTX110 (aqueous panobinostat) in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). Neuro Oncol. 25, 2074–2086 (2023)." href="#ref-CR34" id="ref-link-section-d63664714e3107">34</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" title="Mueller, S. et al. Mass cytometry detects H3.3K27M-specific vaccine responses in diffuse midline glioma. J. Clin. Invest. 130, 6325–6337 (2020)." href="#ref-CR35" id="ref-link-section-d63664714e3107_1">35</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Gardner, S. L. et al. Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy. Neurooncol. Adv. 4, vdac143 (2022)." href="/articles/s41586-024-08171-9#ref-CR36" id="ref-link-section-d63664714e3110">36</a></sup>. The present study establishes GD2-CAR T cell therapy as a promising modality for a historically lethal CNS cancer. The rate of clinical improvements and tumour regressions on MRI imaging, including a complete response by RANO 2.0 criteria sustained for over 30 months and throughout the duration of this report, is reason for cautious optimism, both for DIPG/sDMG therapy and, more broadly, for CAR T cell therapy of solid tumours. Therapeutic activity was clearly demonstrated in several patients, based on tumour regression by imaging and improvements in neurological symptoms. Whether GD2-CAR T cell therapy favourably impacts overall survival is difficult to discern, given that the eligibility criteria excluded patients with lower performance status, the need for steroid therapy, bulky thalamic or cerebellar tumour involvement and other factors. Moreover, multiple patients demonstrated MAPK pathway and ATRX or DAXX mutations, which can be associated with relatively longer survival<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Roberts, H. J. et al. Clinical, genomic, and epigenomic analyses of H3K27M-mutant diffuse midline glioma long-term survivors reveal a distinct group of tumors with MAPK pathway alterations. Acta Neuropathol. 146, 849–852 (2023)." href="/articles/s41586-024-08171-9#ref-CR37" id="ref-link-section-d63664714e3114">37</a></sup> and more localized disease<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Pathania, M. et al. H3.3(K27M) cooperates with Trp53 loss and PDGFRA gain in mouse embryonic neural progenitor cells to induce invasive high-grade gliomas. Cancer Cell 32, 684–700 (2017)." href="/articles/s41586-024-08171-9#ref-CR38" id="ref-link-section-d63664714e3118">38</a></sup>. The effects of GD2-CAR T cell therapy on overall survival will need to be assessed in future Phase II trials.</p><p>The toxicities observed here were generally anticipated, but with some notable observations. Cytokine release syndrome was dose limiting following IV infusion of GD2-CART for DIPG/DMG. By contrast, CRS did not commonly complicate ICV infusions. Given that the antitumour immune response occurs within the CNS in both contexts, this marked difference in systemic cytokine responses leading to CRS following IV administration is somewhat unexpected, and underscores the unique features of immune cell trafficking into and out of the CNS only recently coming to light<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Mazzitelli, J. A. et al. Skull bone marrow channels as immune gateways to the central nervous system. Nat. Neurosci. 26, 2052–2062 (2023)." href="/articles/s41586-024-08171-9#ref-CR39" id="ref-link-section-d63664714e3125">39</a>,<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Salvador, A. F. M., Abduljawad, N. & Kipnis, J. Meningeal lymphatics in central nervous system diseases. Annu. Rev. Neurosci. 47, 323–344 (2024)." href="/articles/s41586-024-08171-9#ref-CR40" id="ref-link-section-d63664714e3128">40</a></sup>. Unexpectedly, ICANS was observed only following IV administration, but not with ICV infusions, despite the higher levels of cytokines/chemokines evident in CSF following ICV GD2-CART infusions. Whereas the rate of intratumoural haemorrhage observed in this cohort (1 of 11) is in line with the natural history of this disease<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Broniscer, A. et al. Intratumoral hemorrhage among children with newly diagnosed, diffuse brainstem glioma. Cancer 106, 1364–1371 (2006)." href="/articles/s41586-024-08171-9#ref-CR30" id="ref-link-section-d63664714e3132">30</a></sup>, future study is needed to determine whether CAR T cell therapy alters the risk of intratumoural bleeding. Inflammation of neural structures can cause oedema with consequent mechanical complications such as obstruction of CSF flow, and immune signalling can also affect neuronal function. Varying grades of TIAN<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Mahdi, J. et al. Tumor inflammation-associated neurotoxicity. Nat. Med. 29, 803–810 (2023)." href="/articles/s41586-024-08171-9#ref-CR28" id="ref-link-section-d63664714e3136">28</a></sup> occurred commonly, as would be expected with inflammation of tumours located in structurally constrained and functionally eloquent neuroanatomical areas such as the brainstem and spinal cord. Concordantly, tumours located in the lower brainstem were associated with more severe TIAN. TIAN was transient and manageable with intensive support. In general, earlier infusions and larger tumours were associated with greater toxicity. The correlation of more severe TIAN with higher levels of cytokines/chemokines related to myeloid response, such as MCP1 or CCL2, raises the prospect that myeloid cells may contribute to neurological symptoms induced by CAR T cell therapy for CNS tumours, a hypothesis that requires testing in future studies. The observed decrease in TIAN severity with repeated infusions is notable and could be due to decreased tumour burden with repeated infusions, increased immunomodulatory or immunosuppressive mechanisms in the tumour microenvironment, or both.</p><p>Given the promising results noted in arm A with repeated ICV administration of GD2-CAR T cells, but with dose-limiting CRS following IV administration at high dose levels, we have now initiated arms B and C to test ICV-only administration with and without lymphodepleting chemotherapy. Given the burden of monthly infusions on the patient, we have also included formalized assessments of quality of life and patient-reported outcomes in arms B and C. Ongoing and future work will define the optimal route of administration, the role of lymphodepleting chemotherapy and potential combination strategies for optimization of this promising therapy to achieve more complete and durable responses for children and adults with H3K27M-mutated diffuse midline gliomas.</p></div></div></section><section data-title="Methods"><div class="c-article-section" id="Sec11-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec11">Methods</h2><div class="c-article-section__content" id="Sec11-content"><h3 class="c-article__sub-heading" id="Sec12">Human subjects</h3><p>The Stanford Institutional Review Board approved this trial, which was registered with <a href="http://ClinicalTrials.gov">ClinicalTrials.gov</a> (<a href="https://clinicaltrials.gov/study/NCT04196413">NCT04196413</a>). Informed patient or parent consent and child assent were obtained. Included in consent is permission to share the (deidentified) results of the trial in scientific publications or presentations. Permission to publish images, photographs and videos was also obtained.</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec13">Response assessment</h3><p>Clinical response was assessed using the CIS<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022)." href="/articles/s41586-024-08171-9#ref-CR3" id="ref-link-section-d63664714e3177">3</a></sup> generated by protocol-directed neurological examinations performed by a neuro-oncologist at prescribed times following GD2-CAR T cell administration. The CIS represents a simple quantification of the neurological examination, which added or subtracted one point for each symptom/sign that improved or worsened, respectively, from the patient’s preinfusion baseline examination (Supplementary Methods <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM1">5</a>). For patients who received corticosteroid therapy for toxicity management, CIS scoring was deferred until at least 7 days following corticosteroid discontinuation. Imaging responses were assessed by MRI scans of the brain and/or spinal cord with and without gadolinium. Because DMGs are diffusely infiltrative of CNS structures and difficult to measure in linear dimensions, volumetric segmentation of tumour corresponding to abnormal T2 signal was performed by a neuroradiologist to measure radiographic change in tumour volume, consistent with RANO 2.0 recommendations<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Wen, P. Y. et al. RANO 2.0: update to the response assessment in neuro-oncology criteria for high- and low-grade gliomas in adults. J. Clin. Oncol. 41, 33 (2023)." href="/articles/s41586-024-08171-9#ref-CR41" id="ref-link-section-d63664714e3184">41</a></sup>.</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec14">Statistical analysis</h3><p>Sample size estimation was based on clinical considerations and the Phase I 3 + 3 design. The targeted DLT rate was 30% or less. All patients who enroled into arm A and received one infusion of GD2-CAR T cells on trial were included in the analysis. Descriptive statistics were used to summarize baseline patient and disease characteristics, toxicity data and correlative and clinical outcomes. The Shapiro–Wilk test of normality was used to assess normal (Gaussian) distribution of tumour volumetric response data. Overall survival was measured from date of diagnosis to the date that event occurred, or censored at the time of data cut-off. Survival probability was estimated using the Kaplan–Meier method<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="Kaplan, E. M. P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53, 457–481 (1958)." href="/articles/s41586-024-08171-9#ref-CR42" id="ref-link-section-d63664714e3196">42</a></sup>. The confidence interval of median survival time was constructed by the method of Brookmeyer–Crowley<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 43" title="Crowley, R. B. J. A confidence interval for the median survival time. Biometrics 38, 29–41 (1982)." href="/articles/s41586-024-08171-9#ref-CR43" id="ref-link-section-d63664714e3200">43</a></sup>. All comparisons made in correlative outcomes were exploratory. Mann–Whitney <i>U</i>-test was used, with no adjustments made for multiple comparisons. Statistical analyses were conducted using Prism software.</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec15">Correlative studies</h3><p>Peripheral blood and CSF samples were collected before and following IV and ICV infusions to measure cytokine/chemokine levels in blood and CSF, GD2-CART persistence by qPCR and CAR-FACS and cell-free tumour DNA in CSF, as detailed in the previous report of the first four patients<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022)." href="/articles/s41586-024-08171-9#ref-CR3" id="ref-link-section-d63664714e3215">3</a></sup> and reiterated below.</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec16">qPCR measurement of in vivo GD2-CAR expansion</h4><p>Patient blood samples were processed and mononuclear cells viably cryopreserved. DNA was extracted from whole blood (2 × 10<sup>6</sup>–5 × 10<sup>6</sup> peripheral blood mononuclear cells (PBMCs)) using the QIAmp DNA blood Mini Kit (Qiagen, catalogue no. 51306) at baseline and at multiple time points following CAR administration. CAR presence was measured by qPCR using the primer and probe sequences provided below. For the standard curve, a custom Minigene plasmid (IDT) was designed containing a partial GD2.41BB.z sequence and a partial albumin sequence, which served as a control for normalization. The standard curve contained a tenfold serial dilution of plasmid ranging between 5 × 10<sup>8</sup> and 5 × 10<sup>0</sup> copies. Both plasmid and patient DNA from each time point were run in triplicate, with each reaction containing 5 µl of DNA (50 ng total), 200 nM forward and reverse albumin primers (or 300 nM forward and reverse GD2.41BB.z primers), 150 nM probe suspended in 10 µl of TaqMan Fast Universal PCR Master Mix (2X), no AmpErase UNG (Thermo Fisher Scientific) and either 24.5 µl (albumin) or 22.5 µl (GD2.41BB.z) of TE buffer (Invitrogen, catalogue no. AM9935). The Thermo Fisher Scientific QuantStudio 6 Pro Real-time qPCR Instrument was used for qPCR, with 20 µl per reaction. Quality metrics for all qPCR standard curve results were <i>R</i><sup>2</sup> > 0.95 and efficiency 70–110%.</p><p>Albumin results from the plate were normalized to average albumin, then GD2-CAR copy number (copies per 50 ng of DNA), adjusted to albumin and modified to copies per 100 ng of DNA, was calculated by the following equation: copy number (copies per 100 ng of DNA) = 2 × (GD2-CAR copy number × (albumin copy number/average albumin)).</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec17">Real-time flow cytometry assay</h4><p>A high-dimensional, immunophenotyping, flow cytometry panel was designed for immune profiling of CAR T cells in real time. PBMCs were isolated from fresh whole blood by gradient centrifugation on ficoll (Ficoll paque Plus, GE Healthcare, Sigma-Aldrich). Between 2 million and 5 million PBMCs were stained with fixable Live/Dead aqua (Invitrogen) amine-reactive viability stain. Cells were preincubated with Fc block (trustain, BioLegend) for 5 min, then stained at room temperature with fluorochrome-conjugated mAb in a 15-colour, 17-parameter staining combination as previously described<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022)." href="/articles/s41586-024-08171-9#ref-CR3" id="ref-link-section-d63664714e3249">3</a></sup>. Antibody–fluorochrome conjugates used were: anti-CD3-FITC (BioLegend, 0.5 µg of antibody per 1 million cells in 100 µl); anti-CD8-PerCP Cy5.5 (BD Biosciences, 0.5 µg of antibody per 1 million cells in 100 µl); anti-CD45-BV785 (BioLegend, 1 µg of antibody per 1 million cells in 100 µl); anto-CD4-BV711 (BioLegend, 1 µg of antibody per 1 million cells in 100 µl); anti-CD95-BV650 (BioLegend, 0.5 µg of antibody per 1 million cells in 100 µl); CD39-BV605 (BioLegend, 1 µg of antibody per 1 million cells in 100 µl); anti-CD57-BV421 (BioLegend, 1 µg of antibody per 1 million cells in 100 µl); anti-CCR7-BUV805 (BioLegend, 1 µg of antibody per 1 million cells in 100 µl); anti-CD45RA-Alx700 (BioLegend, 0.5 µg of antibody per 1 million cells in 100 µl); anti-GD2-CAR-DyLight650 (custom, clone 1A7, 1 µg of antibody per 1 million cells in 100 µl); anti-CD14-PE-Cy7 (BioLegend, 1 µg of antibody per 1 million cells in 100 µl); anti-CD11b-APC-Cy7 (BioLegend, 1 µg of antibody per 1 million cells in 100 µl); anti-CD33-PE-Dazzle (BioLegend, 5 µl of antibody per 1 million cells in 100 µl); and anti-GD2-PE (BioLegend, 5 µl of antibody per 1 million cells in 100 µl). For determination of the optimal concentration of antibody for staining in the CAR-FACS panel, each fluorochrome-conjugated antibody was titrated to determine the saturating amount of antibody needed to stain a test of 1 million cells. Dose–response curves for each antibody informed the saturating amount of fluorochrome-conjugated antibody required for staining 1 million cells in 100 ml of staining volume.</p><p>CAR-tranduced T cells were used as positive control included in daily staining experiments. Immunostained and fixed cells were acquired on an LSR (BD BioSciences) five-laser (blue, 488 nm; violet, 405 nm; ultraviolet, 355 nm; red, 640 nm; green, 532 nm) analyser. A minimum of 10<sup>6</sup> cells were acquired, unless restricted by the number of cells isolated from 8 ml of whole blood or when acquiring isolated cells from CSF. The assay limit of detection for cells was calculated as 1 in 10<sup>4</sup> of total acquired PBMCs. Representative gating is shown in Extended Data Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig13">10</a>.</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec18">Luminex cytokines</h4><p>Patient blood and CSF samples were collected at predetermined and trigger time points throughout treatment. Samples were spun at 250<i>g</i> for 6 min. Supernatant was frozen at −80 °C until batched for assessment. Cytokine assessment was performed with the Immunoassay Team-Human Immune Monitoring Center at Stanford University. Panels include Luminex–EMD Millipore HIMC H80 (panel 1 is Milliplex HCYTA-60K-PX48; panel 2 is Milliplex HCP2MAG-62K-PX23; panel 3 includes Milliplex HSP1MAG-63K-06 and HADCYMAG-61K-03 (resistin, leptin and hepatocyte growth factor) to generate a nine-plex) and TGF-b (TGFBMAG-64K-03). Kits were purchased from EMD Millipore and used according to the manufacturer’s recommendations, with modifications described. The assay set-up followed the recommended protocol. Briefly, samples were diluted threefold for panels 1 and 2 and tenfold for panel 3. Diluted sample (25 µl) was mixed with antibody-linked magnetic beads in a 96-well plate and incubated overnight at 4 °C with shaking. Both cold and room-temperature incubation steps were performed on an orbital shaker at 500–600 rpm. Plates were washed twice with wash buffer in a Biotek ELx405 washer (BioTek Instruments). Following incubation for 1 h at room temperature with biotinylated detection antibody, streptavidin-PE was added for 30 min with shaking. Plates were washed as described above, and PBS added to wells for reading in the Luminex FlexMap3D Instrument with a lower bound of 50 beads per sample per cytokine. Custom Assay Chex control beads (Radix Biosolutions) were purchased and added to all wells. Wells with a bead count under 50 were flagged, and data with a bead count under 20 were excluded. Data are presented as picograms per millilitre, based on standard curves or heat maps of fold change from the baseline time point. All samples were run in technical duplicate.</p><h3 class="c-article__sub-heading c-article__sub-heading--divider" id="Sec19">Reporting summary</h3><p>Further information on research design is available in the <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM2">Nature Portfolio Reporting Summary</a> linked to this article.</p></div></div></section> </div> <div> <section data-title="Data availability"><div class="c-article-section" id="data-availability-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="data-availability">Data availability</h2><div class="c-article-section__content" id="data-availability-content"> <p><a data-track="click" data-track-label="link" data-track-action="section anchor" href="/articles/s41586-024-08171-9#Sec22">Source data</a> are provided with this paper.</p> </div></div></section><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">Mount, C. 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We also thank Bellicum Pharmaceuticals for providing the GD2-CAR vector and AP1903. We thank Stanford HIMC for performing cytokine assays, and the Cellular Therapy Facility at Stanford for their support of this Phase I clinical trial, including that for cell pharmacy. Funding for the clinical trial was provided by grants from the Parker Institute for Cancer Immunotherapy, CureSearch, the National Cancer Institute (no. R01CA263500) and the California Institute for Regenerative Medicine (no. CLIN2-12595). This work was also supported in part by grants from the St. Baldrick’s Foundation to the Empowering Immunotherapies for Children’s Cancers Cancer team and Alex’s Lemonade Stand Foundation. We acknowledge generous funding by the Virginia and D. K. Ludwig Fund for Cancer Research (M.M. and C. Mackall), ChadTough Defeat DIPG Foundation (M.M. and J. Mahdi), Oscar’s Kids Foundation (M.M.), Arms Wide Open Childhood Cancer Foundation (M.M.), Tough2gether Foundation (M.M.), Storm the Heavens Foundation (M.M.), the DIPG/DMG Research Funding Alliance (M.M.) and the Chambers-Okamura Endowed Directorship for Pediatric Neuro-Immuno-Oncology (M.M.). R.M. was the Taube Distinguished Scholar for Pediatric Immunotherapy at Stanford University School of Medicine, and was supported by the Be Brooks Brave Fund St. Baldrick’s Scholar Award. S.R. was supported by K08CA267057.</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 Neurological Sciences, Stanford University, Stanford, CA, USA</p><p class="c-article-author-affiliation__authors-list">Michelle Monje, Jasia Mahdi, Kristen W. Yeom, Kun-Wei Song, Sonia Partap, Paul G. Fisher & Cynthia J. Campen</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Division of Pediatric Hematology/Oncology/Stem Cell Transplant and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA, USA</p><p class="c-article-author-affiliation__authors-list">Michelle Monje, Robbie Majzner, Liora M. Schultz, Rebecca M. Richards, Valentin Barsan, Jen Kamens, Agnes Reschke, Sean Green, Kara L. Davis, Sneha Ramakrishna & Crystal Mackall</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA</p><p class="c-article-author-affiliation__authors-list">Michelle Monje, Jasia Mahdi, Robbie Majzner, Liora M. Schultz, Rebecca M. Richards, Valentin Barsan, Kun-Wei Song, Jen Kamens, Christina Baggott, Michael Kunicki, Skyler P. Rietberg, Alexandria Sung Lim, Agnes Reschke, Sharon Mavroukakis, Emily Egeler, Jennifer Moon, Shabnum Patel, Harshini Chinnasamy, Courtney Erickson, Ashley Jacobs, Ramya Tunuguntla, Dorota Danuta Klysz, Carley Fowler, Barbara Beebe, Casey Carr, Michelle Fujimoto, Annie Kathleen Brown, Ann-Louise G. Petersen, Warren D. Reynolds, Adam Kuo, Snehit Prabhu, Bita Sahaf, Kara L. Davis, Steven A. Feldman, Sneha Ramakrishna & Crystal Mackall</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">Department of Neurosurgery, Stanford University, Stanford, CA, USA</p><p class="c-article-author-affiliation__authors-list">Michelle Monje, Kristen W. Yeom, Allison K. Duh, Gerald Grant & Laura Prolo</p></li><li id="Aff5"><p class="c-article-author-affiliation__address">Department of Pathology, Stanford University, Stanford, CA, USA</p><p class="c-article-author-affiliation__authors-list">Michelle Monje</p></li><li id="Aff6"><p class="c-article-author-affiliation__address">Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA</p><p class="c-article-author-affiliation__authors-list">Michelle Monje</p></li><li id="Aff7"><p class="c-article-author-affiliation__address">Division of Neuroradiology, Department of Radiology, Stanford University, Stanford, CA, USA</p><p class="c-article-author-affiliation__authors-list">Kristen W. Yeom</p></li><li id="Aff8"><p class="c-article-author-affiliation__address">Cellular Therapy Facility, Stanford Health Care, Palo Alto, CA, USA</p><p class="c-article-author-affiliation__authors-list">Catherine McIntyre, Aman Siddiqui, Nadia Lepori-Bui, Katlin Villar, Kymhuynh Pham, Rachel Bove & Eric Musa</p></li><li id="Aff9"><p class="c-article-author-affiliation__address">Department of Pediatrics, Division of Pediatric Critical Care Medicine, Stanford University, Stanford, CA, US</p><p class="c-article-author-affiliation__authors-list">Lindsey Rasmussen & Timothy T. Cornell</p></li><li id="Aff10"><p class="c-article-author-affiliation__address">Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD, USA</p><p class="c-article-author-affiliation__authors-list">Xiaobu Ye</p></li><li id="Aff11"><p class="c-article-author-affiliation__address">Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA</p><p class="c-article-author-affiliation__authors-list">Crystal Mackall</p></li><li id="Aff12"><p class="c-article-author-affiliation__address">Division of Stem Cell Transplantation and Cell Therapy, Department of Medicine, Stanford University, Stanford, CA, USA</p><p class="c-article-author-affiliation__authors-list">Crystal Mackall</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-Michelle-Monje-Aff1-Aff2-Aff3-Aff4-Aff5-Aff6"><span class="c-article-authors-search__title u-h3 js-search-name">Michelle Monje</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=Michelle%20Monje" 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=Michelle%20Monje" 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=%22Michelle%20Monje%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><li id="auth-Jasia-Mahdi-Aff1-Aff3"><span class="c-article-authors-search__title u-h3 js-search-name">Jasia Mahdi</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=Jasia%20Mahdi" 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=Jasia%20Mahdi" 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=%22Jasia%20Mahdi%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><li id="auth-Robbie-Majzner-Aff2-Aff3"><span class="c-article-authors-search__title u-h3 js-search-name">Robbie Majzner</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=Robbie%20Majzner" 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=Robbie%20Majzner" 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=%22Robbie%20Majzner%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><li id="auth-Kristen_W_-Yeom-Aff1-Aff4-Aff7"><span class="c-article-authors-search__title u-h3 js-search-name">Kristen W. 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Mackall is the IND holder. R.M., C. Mackall and M.M. conceived of the project. S.M., E.E. and C.B. oversaw regulatory affairs. S.M., E.E., M.M., C. Mackall, R.M., S. Partap., C.J.C., J. Mahdi, L.R., T.T.C. and G.G. planned, designed and/or wrote the clinical trial, amendments and treatment protocols. S. Patel., H.C. and S.A.F. performed process development for cellular manufacturing and supervised cellular manufacturing. A.K.B., A.-L.G.P., C. McIntyre, C.F., A.K.D., R.T. and D.D.K. participated in cellular manufacturing and preparation for infusion. R.M., S.R., K.-W.S., L.M.S., R.M.R., V.B., J. Mahdi, A.R., C.B., J. Moon, C.E., S.G., L.R., T.T.C., S. Partap, P.G.F., C.J.C., G.G., L.P., K.L.D., C. Mackall and M.M. participated in patient care. K.W.Y. read MRI images and performed volumetric analysis of MRI scans. C.B., J. Moon, M.K., A.S.L. and M.F. participated in the collection and/or processing of patient samples. V.B., W.D.R. and B.S. performed correlative studies. V.B. designed the ctDNA assay. S.R., S.P.R., S. Prabhu and B.S. analysed correlative studies. C.C. and B.B. provided administrative and programme management support. X.Y. provided statistical contributions. J. Mahdi., S.R., M.M. and C. Mackall prepared figures and wrote the manuscript. All authors reviewed and edited the manuscript. M.M. and C. Mackall supervised all aspects of the work.</p><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding authors</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:mmonje@stanford.edu">Michelle Monje</a>, <a id="corresp-c2" href="mailto:ramakrs@stanford.edu">Sneha Ramakrishna</a> or <a id="corresp-c3" href="mailto:cmackall@stanford.edu">Crystal Mackall</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" id="FPar3">Competing interests</h3> <p>M.M., R.M. and C. Mackall are coinventors on a patent for the use of GD2-CAR T cells in regard to H2K27M gliomas, coordinated through Stanford University. C. Mackall is a coinventor on patents for the use of dasatinib and other small molecules to modulate CAR function and control CAR-associated toxicity, and on several patents related to CAR T cell therapies. C. Mackall holds equity in CARGO Therapeutics, Link Cell Therapies and GBM Newco, which are developing CAR-based therapies, and consults for CARGO, Link, Immatics, Ensoma, GBM NewCo and Red Tree Capital. She receives research funding from Lyell and Tune Therapeutics. R.M. is a cofounder of, and holds equity in, Link Cell Therapies and CARGO Therapeutics, and is a consultant for Lyell Immunopharma, NKarta, Arovella Pharmaceuticals, Innervate Radiopharmaceuticals, Aptorum Group, Gadeta, FATE Therapeutics (Data and Safety Monitoring Board) and Waypoint Bio. S.A.F. holds several patents in the field of cellular immunotherapy. V.B. is an investor and Director at Umoja Biopharma and Arsenal Bio. S.P.R. holds equity in Lyell Immunopharma. M.M. holds equity in MapLight Therapeutics and CARGO Therapeutics. The other authors declare no competing interests.</p> </div></div></section><section data-title="Peer review"><div class="c-article-section" id="peer-review-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="peer-review">Peer review</h2><div class="c-article-section__content" id="peer-review-content"> <h3 class="c-article__sub-heading" id="FPar2">Peer review information</h3> <p><i>Nature</i> thanks Andras Heczey, Misty Jenkins and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM3">Peer reviewer reports</a> are available.</p> </div></div></section><section data-title="Additional information"><div class="c-article-section" id="additional-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="additional-information">Additional information</h2><div class="c-article-section__content" id="additional-information-content"><p><b>Publisher’s note</b> Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p></div></div></section><section data-title="Extended data figures and tables"><div class="c-article-section" id="Sec21-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec21">Extended data figures and tables</h2><div class="c-article-section__content" id="Sec21-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 js-c-reading-companion-figures-item" data-test="supp-item" id="Fig4"><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="extended data fig. 1 gd2-car t cell manufacturing " href="/articles/s41586-024-08171-9/figures/4" data-supp-info-image="//media.springernature.com/lw685/springer-static/esm/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig4_ESM.jpg">Extended Data Fig. 1 GD2-CAR T cell manufacturing process and drug product characterization.</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p><b>a</b>. GD2-CART manufacturing workflow from patient apheresis collection to final drug product harvest across 7 days. <b>b</b>. Schematic representing GD2.4-1BB.CD3<i>ζ</i> CAR containing 14G2α binding domain, CD8α hinge and transmembrane (TM) domain, 4-1BB co-stimulatory domain, and a CD3<i>ζ</i> domain. <b>c</b>. Flow cytometric immunophenotyping of apheresis, CD4<sup>+</sup>/CD8<sup>+</sup> enriched cells, and final drug product demonstrates a predominance of CD3 + T cells and depletion of other subsets. <b>d</b>. The CD4:CD8 ratio was 1.63 ± 1.19 (SD) at apheresis, and 2.48 ± 0.06 (SD) in the GD2-CART final drug product. <b>e</b>. Phenotyping of T-cell subsets shows a predominance of central memory (CM) T cells (CD45RA<sup>−</sup>CCR7<sup>+</sup>), followed by effector memory (EM) cells (CD45RA<sup>−</sup>CCR7<sup>−</sup>), in both CD8<sup>+</sup> (left) and CD4<sup>+</sup> (right) subsets in the final cell product. <b>f</b>. Exhaustion marker expression on CAR<sup>+</sup> and CAR<sup>−</sup> populations reveal no significant differences in CD39, LAG3, and TIM3 expression, while a significantly greater percentage (two-tailed unpaired t-test) of CAR<sup>+</sup> cells express of PD-1. For all graphs, n = 19 GD2-CART products across 12 patients. Data includes 7 additional GD2-CART products re-manufactured for these patients to enable additional infusions. One point = 1 GD2-CART product. Schematics in <b>a</b> and <b>b</b> created using BioRender (<a href="https://biorender.com">https://biorender.com</a>).</p><p><a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM4">Source Data</a></p></div></div><div class="c-article-supplementary__item js-c-reading-companion-figures-item" data-test="supp-item" id="Fig5"><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="extended data fig. 2 consort diagram." href="/articles/s41586-024-08171-9/figures/5" data-supp-info-image="//media.springernature.com/lw685/springer-static/esm/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig5_ESM.jpg">Extended Data Fig. 2 CONSORT diagram.</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>83 patients were assessed for eligibility. Of these, 34 were not eligible, 13 were enrolled, and 36 patients either chose other trials, chose not to enroll on a clinical trial, or progressed to the point of ineligibility while on the waitlist.</p><p><a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM4">Source Data</a></p></div></div><div class="c-article-supplementary__item js-c-reading-companion-figures-item" data-test="supp-item" id="Fig6"><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="extended data fig. 3 functional assessment of gd2-" href="/articles/s41586-024-08171-9/figures/6" data-supp-info-image="//media.springernature.com/lw685/springer-static/esm/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig6_ESM.jpg">Extended Data Fig. 3 Functional assessment of GD2-CAR T cells in vitro<i>.</i></a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p><b>a</b>. Inset: GD2 expression on NALM6-GD2 cell line (acute lymphoblastic leukemia cells engineered to express GD2) showing 38,379 and 0.5 molecules per cell, for stained (red) and unstained (blue) populations, respectively. GD2-CAR T cell reactivity to NALM6-GD2 tumor cells measured by intracellular cytokine secretion (ICS) shows upregulation of CD69, CD107a and secretion of interferon-γ (IFNγ), interleukin-2 (IL-2) and tumor necrosis factor-α (TNFα). <b>b</b>. Incucyte based cytotoxic activity (E:T 1:1), showed that each patient drug product-controlled tumor cell growth within 96 h of co-culture. Each data point is the mean of three technical replicates; error bars, standard error of the mean. <b>c</b>. Transduction efficiency for each patient product plotted as a function of VCN per CAR<sup>+</sup> cell (R<sup>2</sup> = 0.1910). <b>d</b>. No significant difference (ns = p > 0.05, two-tailed unpaired t-test) was observed in GD2-CAR transduction efficiency when manufacturing runs were executed using fresh or frozen patient apheresis material. <b>e</b>. CAR mean fluorescence intensity (MFI) values for CAR T cell expression. For all graphs, n = 19 GD2-CART products across 12 patients. Data includes 7 additional products re-manufactured for these patients to enable additional infusions. For a and c, one point = one GD2-CART product. For b, one line = one GD2-CART product.</p><p><a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM4">Source Data</a></p></div></div><div class="c-article-supplementary__item js-c-reading-companion-figures-item" data-test="supp-item" id="Fig7"><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="extended data fig. 4 tumor volumetric change over " href="/articles/s41586-024-08171-9/figures/7" data-supp-info-image="//media.springernature.com/lw685/springer-static/esm/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig7_ESM.jpg">Extended Data Fig. 4 Tumor volumetric change over time and overall survival.</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p><b>a</b>. QQ plot of Shapiro-Wilk Test Normality Test for Gaussian Distribution (significance level alpha = 0.05). <b>b</b>. Tumor volume as a function of days following first GD2-CART infusion is shown using the same methods used in Figs. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig2">2</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig3">3</a>. Red dots represent timing of measurements; dashed line denotes IV GD2-CART infusion; dotted lines denote ICV GD2-CART infusions. Volumetric data for patients 1, 3 and 4 were presented previously in<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022)." href="/articles/s41586-024-08171-9#ref-CR3" id="ref-link-section-d63664714e3593">3</a></sup>, denoted in that report as DIPG Patient #1, DIPG Patient #2 and DIPG Patient #3, respectively. Volumetric data for patients 6 and 10 are presented in Figs. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig2">2</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig3">3</a>. <b>c</b>. Kaplan-Meier survival curves depicting time from diagnosis to death or data cutoff for all patients (left graph) and those patients with DIPG (right graph, excluding the two patients with spinal cord DMGs). Brookmeyer-Crowley method was used to calculate confidence intervals of median survival time.</p><p><a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM4">Source Data</a></p></div></div><div class="c-article-supplementary__item js-c-reading-companion-figures-item" data-test="supp-item" id="Fig8"><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="extended data fig. 5 gd2-cart levels in blood and " href="/articles/s41586-024-08171-9/figures/8" data-supp-info-image="//media.springernature.com/lw685/springer-static/esm/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig8_ESM.jpg">Extended Data Fig. 5 GD2-CART levels in blood and CSF, and tumor cell-free DNA in CSF.</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p><b>a</b>. GD2-CART copy number was detected using a validated qPCR method and based on a standard curve for GD2-CAR. The average GD2-CAR copy number were normalized to average albumin copies by plate. Copies per 100 ng DNA were depicted as mean ± standard deviation is depicted in blue. We quantified the H3K27M mutation copies per ml of cell free CSF using the ddPCR protocol established previously<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022)." href="/articles/s41586-024-08171-9#ref-CR3" id="ref-link-section-d63664714e3636">3</a></sup>; the mutation number/ml ± standard deviation is depicted in red. The dashed vertical lines designate infusion time points. The bold dashed vertical line designates the initial infusion. Each qPCR data point represents the mean of three technical replicates; each ddPCR data point represents the mean of four technical replicates; error bars, standard error of the mean. <b>b</b>. Percent of CD3 + T cells in CSF that are GD2-CAR-positive T cells. Flow cytometry (FACS) for GD2-CAR, using an anti-idiotype antibody (clone 1A7), demonstrated presence of GD2-CAR T cells (threshold of detection > 0.1% GD2-CART of CD3% T cells) in patient CSF following CAR T cell infusions in CSF samples with sufficient cells to assess by CAR-FACS.</p><p><a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM4">Source Data</a></p></div></div><div class="c-article-supplementary__item js-c-reading-companion-figures-item" data-test="supp-item" id="Fig9"><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="extended data fig. 6 plasma and csf cytokine level" href="/articles/s41586-024-08171-9/figures/9" data-supp-info-image="//media.springernature.com/lw685/springer-static/esm/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig9_ESM.jpg">Extended Data Fig. 6 Plasma and CSF cytokine levels following GD2-CART infusions.</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>CSF cytokine levels after each infusion, expressed as log2 fold change from Day 0 prior to the first infusion for the indicated patient. Timepoints expressed as days from first infusion; (first infusion always administered i.v., subsequent infusions always administered i.c.v.); infusions are separated by a vertical white spacing to indicate the beginning of a new infusion cycle. Infusion number indicated by solid bar above each heatmap. Each square represents one measurement.</p><p><a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM4">Source Data</a></p></div></div><div class="c-article-supplementary__item js-c-reading-companion-figures-item" data-test="supp-item" id="Fig10"><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="extended data fig. 7 correlates of toxicity and re" href="/articles/s41586-024-08171-9/figures/10" data-supp-info-image="//media.springernature.com/lw685/springer-static/esm/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig10_ESM.jpg">Extended Data Fig. 7 Correlates of toxicity and response.</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p><b>a</b>. Correlates of cytokine release syndrome (CRS). Higher plasma MCP-1 and IL2 levels correlate with grade 2 or higher CRS. (CRS grade 2 + , n = 7 patients; CRS grade 0-1, n = 4 patients) <b>b</b>. Correlates of tumor inflammation-associated neurotoxicity (TIAN). Higher CSF levels of MCP-1, IL10 and TNF-alpha correlate with higher grade TIAN (grade 2 and higher). (TIAN grade 2 + , n = 15 patients; TIAN grade 0-1, n = 33 patients) <b>c</b>. CD4:CD8 ratios were calculated based on manufacturing characterization and compared in patients based on best response (responder = decreased or stable tumor volume at best response and clinical improvement, n = 8 patients; non-responder = increased tumor volume at best response, n = 3 patients, as shown in Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41586-024-08171-9#Fig1">1b</a>). <b>d</b>. Correlates of Response. Higher plasma levels of IL2 were found in patients who responded to GD2-CAR T cell therapy (n = 8 patients) compared to non-responders (n = 3 patients). <b>e</b>. Peak levels of IP10, a chemokine secreted in response to interferon-gamma signaling, were decreased at the time of tumor progression compared to timepoints during response in the same patients; dotted line indicates paired values for individual patients (n = 3 patients with paired samples) at time of response (first ICV infusion) and time of progression. Cytokine/chemokine data is represented in pg ml−1 based on standard curves. For statistical analysis, data were grouped by patient, infusion, sample type, and cytokine. The maximum cytokine level per infusion for each patient was compared across a. CRS grading (Grade 0-1 vs Grade 2 + ), b. TIAN grading (Grade 0-1 vs Grade 2 + ), c-d. best response (responder = decreased or stable tumor volume at best response; non-responder = increased tumor volume at best response), and e. progression (responding = first ICV infusion; progressing = first infusion after which tumor progression was evident) using a two-tailed Mann-Whitney U Test. As these analyses were exploratory and sample size was limited, no multiple comparison analysis was conducted.</p><p><a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM4">Source Data</a></p></div></div><div class="c-article-supplementary__item js-c-reading-companion-figures-item" data-test="supp-item" id="Fig11"><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="extended data fig. 8 csf tgf-beta cytokine levels " href="/articles/s41586-024-08171-9/figures/11" data-supp-info-image="//media.springernature.com/lw685/springer-static/esm/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig11_ESM.jpg">Extended Data Fig. 8 CSF TGF-beta cytokine levels following GD2-CART infusions.</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p><b>a</b>. CSF TGF-beta cytokine levels after each infusion, expressed as log2 fold change from Day 0 prior to the first infusion for the indicated patient. Timepoints expressed as days from first infusion; (first infusion always administered i.v., subsequent infusions always administered i.c.v.); infusions are separated by a vertical white spacing to indicate the beginning of a new infusion cycle. Infusion number indicated by solid bar above each heatmap. Each square represents one measurement. <b>b</b>. Absolute TGF-beta1 levels per patient over time. Dotted line represents each GD2-CART infusion for each patient. Data for Patient 012 is missing due to limited CSF sampling for that individual. <b>c</b>. TGF-beta1 levels before and after GD2-CAR T cell therapy (left, n = 10 patients) and at early timepoints following GD2-CART infusion before (“responding”, n = 3 patients) and after progression (right, n = 4 patients). Statistical comparison by two-tailed Mann-Whitney U Test.</p><p><a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM4">Source Data</a></p></div></div><div class="c-article-supplementary__item js-c-reading-companion-figures-item" data-test="supp-item" id="Fig12"><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="extended data fig. 9 clinical improvement scores." href="/articles/s41586-024-08171-9/figures/12" data-supp-info-image="//media.springernature.com/lw685/springer-static/esm/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig12_ESM.jpg">Extended Data Fig. 9 Clinical Improvement Scores.</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p>The clinical improvement scale (CIS) is simple tool to quantify changes in the neurological exam<sup><a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022)." href="/articles/s41586-024-08171-9#ref-CR3" id="ref-link-section-d63664714e3771">3</a></sup> in which each item tested in a comprehensive neurological exam is assigned one point if improved, and −1 point if worse than pre-infusion baseline for each infusion. Clinical improvement scores are assessed one month after each infusion, and compared to the pre-infusion baseline for that infusion. The clinical improvement scale was not assessed if the patient required corticosteroid therapy until at least 7 days from cessation of corticosteroids to avoid confounding effects on neurological function. Each GD2-CAR T cell infusion is treated independently, such that the changes reported compared to the pre-infusion baseline for that infusion. A score of zero (represented as white here) means that there was no clinical change, or that there were an equal number of improved and worsened symptoms/signs following that infusion. Please note that, because the score reflects change after a given infusion, neurological improvement after a previous cycle, with continued benefit but no further improvement, would be annotated with white (no change) in this heatmap. Similarly, improvement in one domain with decreased function in another domain, would also be annotated with white (no change) in this heatmap. Green = better than pre-infusion baseline for that infusion, red = worse than pre-infusion baseline for that infusion. An X indicates that the CIS was not evaluable due to corticosteroid use.</p><p><a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM4">Source Data</a></p></div></div><div class="c-article-supplementary__item js-c-reading-companion-figures-item" data-test="supp-item" id="Fig13"><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="extended data fig. 10 representative gating for fl" href="/articles/s41586-024-08171-9/figures/13" data-supp-info-image="//media.springernature.com/lw685/springer-static/esm/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_Fig13_ESM.jpg">Extended Data Fig. 10 Representative gating for flow cytometry of patient samples.</a></h3><div class="c-article-supplementary__description" data-component="thumbnail-container"><p><b>a</b>. Representative gating of immune subsets throughout manufacturing process. <b>b</b>. Representative gating of phenotypic and functional analyses of manufactured GD2-CART following manufacturing. <b>c</b>. Representative gating of a patient CSF sample by flow cytometry (identical gating was used for PBMC obtained from blood).</p><p><a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41586-024-08171-9#MOESM4">Source Data</a></p></div></div></div></div></div></section><section data-title="Supplementary information"><div class="c-article-section" id="Sec22-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec22">Supplementary information</h2><div class="c-article-section__content" id="Sec22-content"><div data-test="supplementary-info"><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM1"><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="supplementary information" href="https://static-content.springer.com/esm/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_MOESM1_ESM.pdf" data-supp-info-image="">Supplementary Information</a></h3></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM2"><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="reporting summary" href="https://static-content.springer.com/esm/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_MOESM2_ESM.pdf" data-supp-info-image="">Reporting Summary</a></h3></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM3"><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="peer review file" href="https://static-content.springer.com/esm/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_MOESM3_ESM.pdf" data-supp-info-image="">Peer Review File</a></h3></div></div></div></div></section><section data-title="Source data"><div class="c-article-section" id="Sec23-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec23">Source data</h2><div class="c-article-section__content" id="Sec23-content"><div data-test="supplementary-info"><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM4"><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="source data figs. 1–3 and source data extended dat" href="https://static-content.springer.com/esm/art%3A10.1038%2Fs41586-024-08171-9/MediaObjects/41586_2024_8171_MOESM4_ESM.xlsx" data-supp-info-image="">Source Data Figs. 1–3 and Source Data Extended Data Figs. 1–10</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" id="rightslink-content"> <p><b>Open Access</b> This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. 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