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Chimeric antigen receptor-modified T\u2009cells targeting GD2 (GD2-CART) eradicated DMGs in preclinical models\n                    <jats:sup>1<\/jats:sup>\n                    . Arm\u2009A of Phase\u2009I trial no.\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03690193?term=NCT03690193\" ext-link-type=\"uri\">NCT04196413<\/jats:ext-link>\n                    (ref.\u00a0\n                    <jats:sup>2<\/jats:sup>\n                    ) 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\u2009\u00d7\u200910\n                    <jats:sup>6<\/jats:sup>\n                    \u2009kg\n                    <jats:sup>\u2212<\/jats:sup>\n                    <jats:sup>1<\/jats:sup>\n                    ; DL2, 3\u2009\u00d7\u200910\n                    <jats:sup>6<\/jats:sup>\n                    \u2009kg\n                    <jats:sup>\u22121<\/jats:sup>\n                    ) following lymphodepleting chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions (10\u201330\u2009\u00d7\u200910\n                    <jats:sup>6<\/jats:sup>\n                    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                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20093 DL1 (3\u2009DIPG);\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u20098 DL2 (6\u2009DIPG, 2\u2009sDMG)). 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\u2009over\u200930\u2009months 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.\n                  <\/jats:p>","DOI":"10.1038\/s41586-024-08171-9","type":"journal-article","created":{"date-parts":[[2024,11,13]],"date-time":"2024-11-13T12:40:53Z","timestamp":1731501653000},"page":"708-715","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":235,"title":["Intravenous and intracranial GD2-CAR T cells for H3K27M+ diffuse midline 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It is now available under a Creative Commons Attribution 4.0 International license, CC-BY, \u00a9 The Author(s). The error has been corrected in the online version of the article.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 November 2024","order":7,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":8,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":9,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41586-024-08452-3","URL":"https:\/\/doi.org\/10.1038\/s41586-024-08452-3","order":10,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"M.M., R.M. and C.\u00a0Mackall are coinventors on a patent for the use of GD2-CAR T\u2009cells in regard to H2K27M gliomas, coordinated through Stanford University. C.\u00a0Mackall 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\u2009cell therapies. C.\u00a0Mackall 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.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}