Glial injury in neurotoxicity after pediatric CD19-directed chimeric antigen receptor T cell therapy.
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
07 2019
07 2019
Historique:
received:
19
01
2019
revised:
06
05
2019
accepted:
06
05
2019
pubmed:
11
5
2019
medline:
31
3
2020
entrez:
11
5
2019
Statut:
ppublish
Résumé
To test whether systemic cytokine release is associated with central nervous system inflammatory responses and glial injury in immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR)-T cell therapy in children and young adults. We performed a prospective cohort study of clinical manifestations as well as imaging, pathology, CSF, and blood biomarkers on 43 subjects ages 1 to 25 who received CD19-directed CAR/T cells for acute lymphoblastic leukemia (ALL). Neurotoxicity occurred in 19 of 43 (44%) subjects. Nine subjects (21%) had CTCAE grade 3 or 4 neurological symptoms, with no neurotoxicity-related deaths. Reversible delirium, headache, decreased level of consciousness, tremor, and seizures were most commonly observed. Cornell Assessment of Pediatric Delirium (CAPD) scores ≥9 had 94% sensitivity and 33% specificity for grade ≥3 neurotoxicity, and 91% sensitivity and 72% specificity for grade ≥2 neurotoxicity. Neurotoxicity correlated with severity of cytokine release syndrome, abnormal past brain magnetic resonance imaging (MRI), and higher peak CAR-T cell numbers in blood, but not cerebrospinal fluid (CSF). CSF levels of S100 calcium-binding protein B and glial fibrillary acidic protein increased during neurotoxicity, indicating astrocyte injury. There were concomitant increases in CSF white blood cells, protein, interferon-γ (IFNγ), interleukin (IL)-6, IL-10, and granzyme B (GzB), with concurrent elevation of serum IFNγ IL-10, GzB, granulocyte macrophage colony-stimulating factor, macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha, but not IL-6. We did not find direct evidence of endothelial activation. Our data are most consistent with ICANS as a syndrome of systemic inflammation, which affects the brain through compromise of the neurovascular unit and astrocyte injury. ANN NEUROL 2019.
Identifiants
pubmed: 31074527
doi: 10.1002/ana.25502
pmc: PMC9375054
mid: NIHMS1822861
doi:
Substances chimiques
Antigens, CD19
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
42-54Subventions
Organisme : Cancer and St. Baldrick's Pediatric Dream Team Translational Research Grant
ID : SU2C-AACR-DT1113
Pays : International
Organisme : William Lawrence & Blanche Hughes Foundation
Pays : International
Organisme : Ben Towne Foundation
Pays : International
Organisme : Alex's Lemonade Stand Phase I/II Infrastructure Grant
Pays : International
Organisme : Juno Therapeutics
Pays : International
Organisme : Conquer Cancer Foundation Career Development Award
Pays : International
Organisme : NCI NIH HHS
ID : R01 CA136551
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000423
Pays : United States
Organisme : Washington State Life Sciences Discovery Fund
Pays : International
Organisme : NINDS NIH HHS
ID : K12 NS098482
Pays : United States
Informations de copyright
© 2019 American Neurological Association.
Références
Pediatrics. 2018 Jun;141(6):
pubmed: 29716980
Blood. 2017 Jun 22;129(25):3322-3331
pubmed: 28408462
N Engl J Med. 2014 Oct 16;371(16):1507-17
pubmed: 25317870
Nat Med. 2018 Jun;24(6):731-738
pubmed: 29808005
Mol Neurobiol. 2008 Apr-Jun;37(2-3):142-52
pubmed: 18563639
AJR Am J Roentgenol. 2007 Oct;189(4):904-12
pubmed: 17885064
Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):846-51
pubmed: 21187412
Nat Rev Neurosci. 2015 May;16(5):249-63
pubmed: 25891508
Cancer Discov. 2016 Jun;6(6):664-79
pubmed: 27076371
J Neuropathol Exp Neurol. 2018 Oct 1;77(10):877-882
pubmed: 30060228
Cytokine. 2016 Jan;77:227-37
pubmed: 26463515
Cancer Discov. 2017 Dec;7(12):1404-1419
pubmed: 29025771
N Engl J Med. 2018 Feb 1;378(5):449-459
pubmed: 29385376
Nat Med. 2018 Jun;24(6):739-748
pubmed: 29808007
CNS Drugs. 2018 Dec;32(12):1091-1101
pubmed: 30387077
N Engl J Med. 2018 Feb 1;378(5):439-448
pubmed: 29385370
J Biomed Inform. 2009 Apr;42(2):377-81
pubmed: 18929686
PLoS One. 2013 Apr 23;8(4):e62101
pubmed: 23626774
Oncologist. 2018 Aug;23(8):943-947
pubmed: 29622697
Nat Rev Clin Oncol. 2018 Jan;15(1):31-46
pubmed: 28857075
J Biol Chem. 2019 Apr 5;294(14):5430-5437
pubmed: 30804212
Brain Pathol. 2018 May;28(3):372-387
pubmed: 29740942
Trends Pharmacol Sci. 2017 Mar;38(3):291-304
pubmed: 28017362
Blood. 2017 Nov 23;130(21):2295-2306
pubmed: 28924019
Trends Immunol. 2012 Dec;33(12):579-89
pubmed: 22926201
Nat Rev Cancer. 2016 Aug 23;16(9):566-81
pubmed: 27550819
Nat Rev Neurosci. 2006 Jan;7(1):41-53
pubmed: 16371949
Nat Rev Clin Oncol. 2019 Jan;16(1):45-63
pubmed: 30082906
Nat Med. 2018 Jan;24(1):20-28
pubmed: 29155426
Clin Pharmacol Ther. 2018 Apr;103(4):591-598
pubmed: 29171004
Crit Care Med. 2014 Mar;42(3):656-63
pubmed: 24145848
Nat Rev Immunol. 2017 Mar;17(3):179-194
pubmed: 28138136
Lancet Oncol. 2015 Jan;16(1):57-66
pubmed: 25524800
J Neurochem. 2016 Jan;136(2):258-61
pubmed: 26485083
Blood. 2019 Feb 14;133(7):697-709
pubmed: 30463995
Radiographics. 2002 Nov-Dec;22(6):1411-28
pubmed: 12432112
Cancer Discov. 2018 Jun;8(6):750-763
pubmed: 29563103
Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638
pubmed: 30592986
Neuroscientist. 2014 Apr;20(2):160-72
pubmed: 24106265
JCI Insight. 2018 Jan 11;3(1):
pubmed: 29321373
Trends Immunol. 2016 Feb;37(2):154-165
pubmed: 26775912
Ann Neurol. 2018 Oct;84(4):537-546
pubmed: 30178481
Sci Rep. 2017 Feb 03;7:41807
pubmed: 28155917
Cancer Discov. 2018 Aug;8(8):958-971
pubmed: 29880584
Brain Behav Immun. 2017 Feb;60:1-12
pubmed: 26995317
Leukemia. 2018 Feb;32(2):562-565
pubmed: 28990581