Cooperative CAR targeting to selectively eliminate AML and minimize escape.
CAR T cell therapy
ICAHT
IF-BETTER gate
acute myeloid leukemia
chimeric antigen receptor
combinatorial targeting
cooperative CAR
hematotoxicity
off-target toxicity
on-target toxicity
Journal
Cancer cell
ISSN: 1878-3686
Titre abrégé: Cancer Cell
Pays: United States
ID NLM: 101130617
Informations de publication
Date de publication:
13 11 2023
13 11 2023
Historique:
received:
22
03
2023
revised:
20
07
2023
accepted:
15
09
2023
medline:
16
11
2023
pubmed:
7
10
2023
entrez:
6
10
2023
Statut:
ppublish
Résumé
Acute myeloid leukemia (AML) poses a singular challenge for chimeric antigen receptor (CAR) therapy owing to its phenotypic heterogeneity and similarity to normal hematopoietic stem/progenitor cells (HSPCs). Here we expound a CAR strategy intended to efficiently target AML while minimizing HSPC toxicity. Quantification of target expression in relapsed/refractory patient samples and normal HSPCs reveals a therapeutic window for gated co-targeting of ADGRE2 and CLEC12A: We combine an attenuated ADGRE2-CAR with a CLEC12A-chimeric costimulatory receptor (ADCLEC.syn1) to preferentially engage ADGRE2
Identifiants
pubmed: 37802054
pii: S1535-6108(23)00326-4
doi: 10.1016/j.ccell.2023.09.010
pii:
doi:
Substances chimiques
CLEC12A protein, human
0
Receptors, Mitogen
0
Lectins, C-Type
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
1871-1891.e6Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA254838
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests Memorial Sloan Kettering has submitted a patent application (WO2022232016A2) based in part on results presented in this manuscript (M.Sa., S.H., and J.M.-S. are listed among the inventors). M.Sa. and S.H. report research support and research funding from Takeda Pharmaceuticals related to the present research. M.Sa. reports research funding from Atara Biotherapeutics, Fate Therapeutics, and Mnemo Therapeutics unrelated to the present research. M.Sa. and I.R. are scientific cofounders of Mnemo Therapeutics. I.R. reports research funding from Atara Biotherapeutics, Takeda Pharmaceuticals; ownership/equity interests at Fate Therapeutics and Mnemo Therapeutics; intellectual property rights at Juno Therapeutics. K.F., M.R.N., and I.R. report employment at Takeda Pharmaceuticals. M.Su. declares the following competing interests: Novartis: Consultancy, Research Funding; Janssen: Consultancy; Seattle Genetics: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding. J.H.P. declares the following competing interest: research funding support from Takeda Pharmaceuticals, Fate Therapeutics, Genentech, InCyte and Servier; Consultancy from Amgen, Autolus, BMS, Curocel, Kite, Legend Biotech, Minerva, Pfizer, Servier, Sobi, and Takeda Pharmaceuticals; and serves on Scientific Advisory Board of Allogene, Artiva Biotherapeutics, and GC Cell Corporation.