The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells.
Animals
Cytokine Release Syndrome
/ immunology
Dasatinib
/ pharmacology
Dexamethasone
/ pharmacology
Female
Humans
Lymphocyte Activation
/ drug effects
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
/ metabolism
Mice, SCID
Phosphorylation
/ drug effects
Protein Kinase Inhibitors
/ pharmacology
Receptors, Antigen, T-Cell
/ metabolism
T-Lymphocytes
/ drug effects
Journal
Science translational medicine
ISSN: 1946-6242
Titre abrégé: Sci Transl Med
Pays: United States
ID NLM: 101505086
Informations de publication
Date de publication:
03 07 2019
03 07 2019
Historique:
received:
23
07
2018
revised:
04
03
2019
accepted:
30
05
2019
entrez:
5
7
2019
pubmed:
5
7
2019
medline:
25
7
2020
Statut:
ppublish
Résumé
Immunotherapy with chimeric antigen receptor (CAR)-engineered T cells can be effective against advanced malignancies. CAR T cells are "living drugs" that require technologies to enable physicians (and patients) to maintain control over the infused cell product. Here, we demonstrate that the tyrosine kinase inhibitor dasatinib interferes with the lymphocyte-specific protein tyrosine kinase (LCK) and thereby inhibits phosphorylation of CD3ζ and ζ-chain of T cell receptor-associated protein kinase 70 kDa (ZAP70), ablating signaling in CAR constructs containing either CD28_CD3ζ or 4-1BB_CD3ζ activation modules. As a consequence, dasatinib induces a function-off state in CD8
Identifiants
pubmed: 31270272
pii: 11/499/eaau5907
doi: 10.1126/scitranslmed.aau5907
pmc: PMC7523030
mid: NIHMS1622135
pii:
doi:
Substances chimiques
Protein Kinase Inhibitors
0
Receptors, Antigen, T-Cell
0
Dexamethasone
7S5I7G3JQL
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
EC 2.7.10.2
Dasatinib
RBZ1571X5H
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
Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
Informations de copyright
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Références
Science. 1997 Jun 13;276(5319):1719-24
pubmed: 9180086
J Biol Chem. 1998 Dec 25;273(52):34970-5
pubmed: 9857028
N Engl J Med. 2018 Jul 5;379(1):64-73
pubmed: 29972754
Cancer Res. 2006 Jun 1;66(11):5790-7
pubmed: 16740718
Cancer Chemother Pharmacol. 2008 Mar;61(3):365-76
pubmed: 17429625
Blood. 2005 Jun 1;105(11):4247-54
pubmed: 15728125
Sci Transl Med. 2016 Sep 7;8(355):355ra116
pubmed: 27605551
Mol Ther. 2019 Feb 6;27(2):287-299
pubmed: 30573301
Hum Gene Ther. 2004 Jan;15(1):63-76
pubmed: 14965378
PLoS One. 2015 Dec 23;10(12):e0144787
pubmed: 26700307
Nat Med. 2019 Jan;25(1):82-88
pubmed: 30559421
Nature. 2017 May 24;545(7655):423-431
pubmed: 28541315
Nat Rev Clin Oncol. 2018 Jan;15(1):47-62
pubmed: 28925994
J Clin Invest. 2016 Nov 1;126(11):4262-4272
pubmed: 27760047
N Engl J Med. 2018 Feb 1;378(5):449-459
pubmed: 29385376
Nat Med. 2018 Jun;24(6):739-748
pubmed: 29808007
Cancer Immunol Immunother. 2007 Oct;56(10):1551-63
pubmed: 17310380
Nat Med. 2018 Jun;24(6):731-738
pubmed: 29808005
Clin Immunol. 2008 Jun;127(3):330-9
pubmed: 18395492
Drug Metab Dispos. 2008 Jul;36(7):1357-64
pubmed: 18420784
Blood. 2012 Jan 5;119(1):72-82
pubmed: 22031866
Blood. 2017 Nov 23;130(21):2295-2306
pubmed: 28924019
Nature. 2017 Mar 2;543(7643):113-117
pubmed: 28225754
Cancer Immunol Res. 2015 Feb;3(2):125-35
pubmed: 25212991
Nature. 2017 May 25;545(7655):452-456
pubmed: 28514453