NKT Cells Coexpressing a GD2-Specific Chimeric Antigen Receptor and IL15 Show Enhanced
Animals
Apoptosis
Cell Proliferation
Cytotoxicity, Immunologic
/ immunology
Gangliosides
/ immunology
Humans
Immunotherapy, Adoptive
/ methods
Interleukin-15
/ immunology
Lymphocyte Activation
/ immunology
Mice
Mice, Inbred NOD
Mice, SCID
Natural Killer T-Cells
/ immunology
Neuroblastoma
/ immunology
Receptors, Antigen, T-Cell
/ immunology
Receptors, Chimeric Antigen
/ immunology
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 12 2019
01 12 2019
Historique:
received:
01
02
2019
revised:
05
08
2019
accepted:
27
08
2019
pubmed:
6
9
2019
medline:
22
9
2020
entrez:
6
9
2019
Statut:
ppublish
Résumé
Vα24-invariant natural killer T cells (NKT) are attractive carriers for chimeric antigen receptors (CAR) due to their inherent antitumor properties and preferential localization to tumor sites. However, limited persistence of CAR-NKTs in tumor-bearing mice is associated with tumor recurrence. Here, we evaluated whether coexpression of the NKT homeostatic cytokine IL15 with a CAR enhances the Human primary NKTs were Coexpression of IL15 with either costimulatory domain increased CAR-NKT absolute numbers. However, constructs containing 4-1BB induced excessive activation-induced cell death and reduced numeric expansion of NKTs compared with respective CD28-based constructs. Further evaluation of CD28-based GD2.CAR and GD2.CAR.15 showed that coexpression of IL15 led to reduced expression levels of exhaustion markers in NKTs and increased multiround Our results informed selection of the CD28-based GD2.CAR.15 construct for clinical testing and led to initiation of a first-in-human CAR-NKT cell clinical trial (NCT03294954).
Identifiants
pubmed: 31484667
pii: 1078-0432.CCR-19-0421
doi: 10.1158/1078-0432.CCR-19-0421
pmc: PMC6891170
mid: NIHMS1539042
doi:
Substances chimiques
Gangliosides
0
Interleukin-15
0
Receptors, Antigen, T-Cell
0
Receptors, Chimeric Antigen
0
ganglioside, GD2
65988-71-8
Banques de données
ClinicalTrials.gov
['NCT03294954']
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
7126-7138Subventions
Organisme : NCI NIH HHS
ID : P30 CA016086
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA116548
Pays : United States
Organisme : NIH HHS
ID : S10 OD020066
Pays : United States
Informations de copyright
©2019 American Association for Cancer Research.
Références
J Clin Invest. 2016 Jun 1;126(6):2341-55
pubmed: 27183388
Nat Med. 2015 Jun;21(6):581-90
pubmed: 25939063
Cytometry A. 2011 Feb;79(2):167-74
pubmed: 21265010
Blood. 2004 Dec 15;104(13):4150-6
pubmed: 15328159
Nat Med. 2008 Nov;14(11):1264-70
pubmed: 18978797
J Clin Oncol. 2004 Sep 1;22(17):3549-57
pubmed: 15337804
Clin Immunol. 2011 Aug;140(2):119-29
pubmed: 21095162
J Clin Oncol. 2015 Jan 1;33(1):74-82
pubmed: 25403209
N Engl J Med. 2014 Oct 16;371(16):1507-17
pubmed: 25317870
Lancet. 2015 Feb 7;385(9967):517-528
pubmed: 25319501
Immunol Rev. 2014 Jan;257(1):107-26
pubmed: 24329793
J Exp Med. 2005 Nov 7;202(9):1279-88
pubmed: 16275765
Nat Rev Clin Oncol. 2018 Jan;15(1):31-46
pubmed: 28857075
J Exp Med. 2002 Mar 4;195(5):637-41
pubmed: 11877486
Blood. 2002 Jun 1;99(11):4166-73
pubmed: 12010822
Cancer J Sci Am. 1997 Dec;3 Suppl 1:S121-7
pubmed: 9457407
Blood. 2014 Oct 30;124(18):2824-33
pubmed: 25049283
J Clin Invest. 2016 Jun 1;126(6):2123-38
pubmed: 27111235
Cell. 2017 Feb 9;168(4):724-740
pubmed: 28187291
Blood. 2013 Jun 27;121(26):5154-7
pubmed: 23678006
Nat Immunol. 2002 Oct;3(10):966-74
pubmed: 12244311
J Clin Invest. 2012 Jun;122(6):2221-33
pubmed: 22565311
Blood. 2011 Dec 1;118(23):6050-6
pubmed: 21984804
J Clin Invest. 2009 Jun;119(6):1524-36
pubmed: 19411762
Immunol Lett. 2017 Oct;190:159-168
pubmed: 28823521
Blood. 2006 Dec 1;108(12):3890-7
pubmed: 16926291
Blood. 2018 Mar 8;131(10):1045-1052
pubmed: 29358181
Blood. 2012 Mar 22;119(12):2709-20
pubmed: 22160384
J Immunol. 2018 Oct 1;201(7):2141-2153
pubmed: 30111631
Clin Cancer Res. 2019 May 1;25(9):2915-2924
pubmed: 30617136
Cell Rep. 2017 Oct 3;21(1):17-26
pubmed: 28978471
Cancer Immunol Res. 2018 Jan;6(1):36-46
pubmed: 29180536
Front Immunol. 2018 Jun 18;9:1355
pubmed: 29967609
Front Immunol. 2018 Oct 26;9:2486
pubmed: 30416506
Mol Cancer Ther. 2018 Sep;17(9):1795-1815
pubmed: 30181329
Mol Ther. 2017 Aug 2;25(8):1769-1781
pubmed: 28668320
N Engl J Med. 2010 Sep 30;363(14):1324-34
pubmed: 20879881
Mol Ther. 2017 Sep 6;25(9):2214-2224
pubmed: 28602436
Cancer Res. 1977 May;37(5):1364-71
pubmed: 856461
J Exp Med. 2004 May 3;199(9):1213-21
pubmed: 15123743
BMC Cancer. 2017 Aug 17;17(1):551
pubmed: 28818060
Hum Mol Genet. 2015 Oct 15;24(R1):R67-73
pubmed: 26160910
Cancer Res. 2001 Aug 15;61(16):6185-93
pubmed: 11507071