Activation priming and cytokine polyfunctionality modulate the enhanced functionality of low-affinity CD19 CAR T cells.
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
09 05 2023
09 05 2023
Historique:
accepted:
09
11
2022
received:
05
07
2022
medline:
1
5
2023
pubmed:
2
12
2022
entrez:
1
12
2022
Statut:
ppublish
Résumé
We recently described a low-affinity second-generation CD19 chimeric antigen receptor (CAR) CAT that showed enhanced expansion, cytotoxicity, and antitumor efficacy compared with the high-affinity (FMC63-based) CAR used in tisagenlecleucel, in preclinical models. Furthermore, CAT demonstrated an excellent toxicity profile, enhanced in vivo expansion, and long-term persistence in a phase 1 clinical study. To understand the molecular mechanisms behind these properties of CAT CAR T cells, we performed a systematic in vitro characterization of the transcriptomic (RNA sequencing) and protein (cytometry by time of flight) changes occurring in T cells expressing low-affinity vs high-affinity CD19 CARs following stimulation with CD19-expressing cells. Our results show that CAT CAR T cells exhibit enhanced activation to CD19 stimulation and a distinct transcriptomic and protein profile, with increased activation and cytokine polyfunctionality compared with FMC63 CAR T cells. We demonstrate that the enhanced functionality of low-affinity CAT CAR T cells is a consequence of an antigen-dependent priming induced by residual CD19-expressing B cells present in the manufacture.
Identifiants
pubmed: 36453632
pii: 493357
doi: 10.1182/bloodadvances.2022008490
pmc: PMC10182295
doi:
Substances chimiques
Cytokines
0
Receptors, Chimeric Antigen
0
Adaptor Proteins, Signal Transducing
0
Antigens, CD19
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1725-1738Informations de copyright
© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
Références
Nat Med. 2015 Jun;21(6):581-90
pubmed: 25939063
Cancer Res. 2006 Nov 15;66(22):10995-1004
pubmed: 17108138
Nat Med. 2019 Sep;25(9):1408-1414
pubmed: 31477906
Cancer Cell. 2020 Feb 10;37(2):216-225.e6
pubmed: 32004441
Nat Commun. 2020 Jan 10;11(1):219
pubmed: 31924795
Oncoimmunology. 2015 Aug 20;5(1):e1072671
pubmed: 26942092
J Immunol. 2006 May 15;176(10):5975-87
pubmed: 16670306
Cytometry A. 2015 Jul;87(7):636-45
pubmed: 25573116
STAR Protoc. 2022 Feb 09;3(1):101174
pubmed: 35199038
Eur J Immunol. 2010 Aug;40(8):2211-20
pubmed: 20540114
J Immunol. 2004 Dec 15;173(12):7647-53
pubmed: 15585893
Blood. 2014 Jul 10;124(2):188-95
pubmed: 24876563
Cancer Res. 2015 Sep 1;75(17):3505-18
pubmed: 26330164
Genomics Proteomics Bioinformatics. 2019 Apr;17(2):129-139
pubmed: 31229590
PLoS One. 2014 Feb 10;9(2):e85328
pubmed: 24520316
J Immunother Cancer. 2021 May;9(5):
pubmed: 34006631
J Clin Oncol. 2021 Oct 20;39(30):3352-3363
pubmed: 34464155
Blood. 2018 Aug 23;132(8):804-814
pubmed: 29895668
Trends Immunol. 2002 Dec;23(12):592-5
pubmed: 12464571
Cancer Immunol Res. 2015 Apr;3(4):356-67
pubmed: 25600436
Curr Hematol Malig Rep. 2018 Oct;13(5):396-406
pubmed: 30120708
MAbs. 2020 Jan-Dec;12(1):1688616
pubmed: 31852337
Nature. 2006 Apr 13;440(7086):890-5
pubmed: 16612374
J Immunol. 2001 Mar 1;166(5):2917-21
pubmed: 11207239
Nat Med. 2021 Aug;27(8):1419-1431
pubmed: 34312556
Nat Med. 2021 May;27(5):842-850
pubmed: 33888899
Cell Rep. 2017 Oct 3;21(1):17-26
pubmed: 28978471
Int Immunol. 2007 Apr;19(4):345-54
pubmed: 17329235
Front Immunol. 2018 Oct 26;9:2486
pubmed: 30416506
Blood. 2006 Jun 15;107(12):4781-9
pubmed: 16467198
Cancer Discov. 2017 Dec;7(12):1404-1419
pubmed: 29025771
Curr Pharm Biotechnol. 2018;19(1):5-18
pubmed: 29667553
Blood. 2016 Jun 16;127(24):2980-90
pubmed: 27118452
PLoS One. 2016 Mar 23;11(3):e0151859
pubmed: 27008164
Cancer Res. 2015 Sep 1;75(17):3596-607
pubmed: 26330166
Nat Commun. 2021 Jan 18;12(1):409
pubmed: 33462245
Nat Rev Immunol. 2012 Mar 16;12(4):306-15
pubmed: 22421787
Nature. 1995 May 11;375(6527):148-51
pubmed: 7753171
J Immunol. 2002 Jan 15;168(2):763-70
pubmed: 11777970