ROR1-targeting switchable CAR-T cells for cancer therapy.
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
10
01
2022
accepted:
08
07
2022
revised:
07
07
2022
pubmed:
22
7
2022
medline:
24
8
2022
entrez:
21
7
2022
Statut:
ppublish
Résumé
The success of chimeric antigen receptor T cell (CAR-T) therapy in the treatment of hematologic malignancies has prompted the development of numerous CAR-T technologies, including switchable CAR-T (sCAR-T) systems that combine a universal CAR-T with bispecific adapter proteins. Owing to their controllability and versatility, sCAR-Ts have received considerable attention. To explore the therapeutic utility of sCAR-Ts targeting the receptor tyrosine kinase ROR1, which is expressed in hematologic and solid malignancies, and to identify bispecific adaptor proteins that efficiently mediate universal CAR-T engagement, a panel of switches based on ROR1-targeting Fabs with different epitopes and affinities was compared in in vitro and in vivo models of ROR1-expressing cancers. For switches targeting overlapping or identical epitopes, potency correlated with affinity. Surprisingly, however, we identified a switch targeting a unique epitope with low affinity but mediating potent and selective antitumor activity in vitro and in vivo. Converted to a conventional CAR-T, the same anti-ROR1 mAb (324) outperformed a clinically investigated conventional CAR-T that is based on an anti-ROR1 mAb (R12) with ~200-fold higher affinity. Thus, demonstrating therapeutic utility on their own, sCAR-Ts also facilitate higher throughput screening for the identification of conventional CAR-T candidates for preclinical and clinical studies.
Identifiants
pubmed: 35859167
doi: 10.1038/s41388-022-02416-5
pii: 10.1038/s41388-022-02416-5
pmc: PMC9398970
mid: NIHMS1824060
doi:
Substances chimiques
Epitopes
0
Receptors, Chimeric Antigen
0
ROR1 protein, human
EC 2.7.10.1
Receptor Tyrosine Kinase-like Orphan Receptors
EC 2.7.10.1
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
4104-4114Subventions
Organisme : NCI NIH HHS
ID : R21 CA229961
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA204484
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA174844
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA263240
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA181258
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
Références
J Am Chem Soc. 2020 Apr 8;142(14):6554-6568
pubmed: 32191035
Curr Opin Immunol. 2015 Apr;33:9-15
pubmed: 25621840
Blood. 2011 Aug 4;118(5):1255-63
pubmed: 21653320
Cells. 2021 Jan 12;10(1):
pubmed: 33445713
Am J Hematol. 2019 May;94(S1):S3-S9
pubmed: 30680780
Cancers (Basel). 2020 May 21;12(5):
pubmed: 32455621
Proc Natl Acad Sci U S A. 2016 Jan 26;113(4):E459-68
pubmed: 26759369
Sci Rep. 2015 Jul 20;5:10654
pubmed: 26190439
Cancer Res. 2015 Sep 1;75(17):3596-607
pubmed: 26330166
J Immunol. 2004 Dec 15;173(12):7647-53
pubmed: 15585893
Cancer Cell. 2020 Oct 12;38(4):473-488
pubmed: 32735779
Blood. 2010 Nov 25;116(22):4532-41
pubmed: 20702778
Nat Rev Drug Discov. 2020 Mar;19(3):185-199
pubmed: 31900462
Cancer Cell. 2019 Mar 18;35(3):489-503.e8
pubmed: 30889382
MAbs. 2019 May/Jun;11(4):621-631
pubmed: 30892136
J Biol Chem. 2004 Apr 30;279(18):18870-7
pubmed: 14754898
Clin Cancer Res. 2008 Jan 15;14(2):396-404
pubmed: 18223214
Sci Adv. 2020 May 20;6(21):eaaz3223
pubmed: 32637585
Leukemia. 2010 Jun;24(6):1160-70
pubmed: 20428207
J Exp Clin Cancer Res. 2018 Jul 21;37(1):163
pubmed: 30031396
Angew Chem Int Ed Engl. 2016 Jun 20;55(26):7520-4
pubmed: 27145250
Nat Rev Cancer. 2021 Mar;21(3):145-161
pubmed: 33483715
Cancer Immunol Res. 2015 Feb;3(2):206-16
pubmed: 25355068
Expert Opin Ther Targets. 2019 May;23(5):447-456
pubmed: 30935250
PLoS One. 2011;6(6):e21018
pubmed: 21698301
Semin Cancer Biol. 2014 Dec;29:21-31
pubmed: 25068995
J Immunol. 2007 Apr 1;178(7):4650-7
pubmed: 17372024
Nat Med. 2019 Sep;25(9):1408-1414
pubmed: 31477906
Antib Ther. 2021 Oct 15;4(4):222-227
pubmed: 34805745
Mol Ther. 2002 Apr;5(4):479-84
pubmed: 11945076
Science. 2018 Mar 23;359(6382):1361-1365
pubmed: 29567707
Science. 2015 Oct 16;350(6258):aab4077
pubmed: 26405231
Cancer Cell. 2021 Feb 8;39(2):193-208.e10
pubmed: 33357452
Mol Ther. 2019 Feb 6;27(2):287-299
pubmed: 30573301
J Immunol. 2010 May 1;184(9):4936-46
pubmed: 20351194
Proc Natl Acad Sci U S A. 2018 Nov 13;115(46):E10898-E10906
pubmed: 30373813
Proc Natl Acad Sci U S A. 2018 Jun 12;115(24):E5467-E5476
pubmed: 29844189
Expert Opin Ther Targets. 2015 Jul;19(7):941-55
pubmed: 25835638
Cancer Immunol Res. 2015 Feb;3(2):125-35
pubmed: 25212991
J Biol Chem. 2020 May 1;295(18):5995-6006
pubmed: 32193207
Nat Commun. 2019 Jun 18;10(1):2681
pubmed: 31213606
Front Oncol. 2019 Mar 26;9:176
pubmed: 30984613
J Mol Biol. 2017 Sep 15;429(19):2954-2973
pubmed: 28818634
Curr Opin Immunol. 2022 Feb;74:190-198
pubmed: 34389174
EBioMedicine. 2020 Aug;58:102931
pubmed: 32739874
Crit Rev Oncol Hematol. 2021 Mar;159:103239
pubmed: 33497760
Cell Stem Cell. 2018 Jun 01;22(6):951-959.e3
pubmed: 29859176
Angew Chem Int Ed Engl. 2020 Jul 13;59(29):12178-12185
pubmed: 32329959
Nat Commun. 2019 Jul 17;10(1):3137
pubmed: 31316055
PLoS One. 2012;7(12):e52655
pubmed: 23285131
Front Oncol. 2021 May 28;11:680834
pubmed: 34123850
Acta Pharm Sin B. 2021 May;11(5):1129-1147
pubmed: 34094824
Mol Cancer Ther. 2021 May;20(5):872-884
pubmed: 33649106
Clin Cancer Res. 2017 Jun 15;23(12):3061-3071
pubmed: 27852699
J Pharmacol Pharmacother. 2013 Oct;4(4):303-6
pubmed: 24250214
Int J Mol Sci. 2019 Mar 14;20(6):
pubmed: 30875739
Cell. 2018 May 31;173(6):1426-1438.e11
pubmed: 29706540
Cell. 2022 May 12;185(10):1745-1763.e22
pubmed: 35483375
Methods Mol Biol. 2020;2086:1-10
pubmed: 31707664
Clin Cancer Res. 2013 Jun 15;19(12):3153-64
pubmed: 23620405
Gut. 2019 Jun;68(6):1052-1064
pubmed: 30121627