Cooperative CAR targeting to selectively eliminate AML and minimize escape.

Autor:	Haubner S; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Mansilla-Soto J; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Nataraj S; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Kogel F; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Chang Q; Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., de Stanchina E; Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Lopez M; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Ng MR; Takeda Development Center Americas, Inc., Lexington, MA 02421, USA., Fraser K; Takeda Development Center Americas, Inc., Lexington, MA 02421, USA., Subklewe M; Department of Medicine III, University Hospital, LMU Munich, 81377 Munich, Germany., Park JH; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Cellular Therapy Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Wang X; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Rivière I; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Michael G. Harris Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Sadelain M; Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: m-sadelain@ski.mskcc.org.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2023 Nov 13; Vol. 41 (11), pp. 1871-1891.e6. Date of Electronic Publication: 2023 Oct 05.
DOI:	10.1016/j.ccell.2023.09.010
Abstrakt:	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 pos CLEC12A pos leukemic stem cells over ADGRE2 low CLEC12A neg normal HSPCs. ADCLEC.syn1 prevents antigen escape in AML xenograft models, outperforms the ADGRE2-CAR alone and eradicates AML despite proximate myelopoiesis in humanized mice. Off-target HSPC toxicity is similar to that of a CD19-CAR and can be mitigated by reducing CAR T cell-derived interferon-γ. Overall, we demonstrate the ability of target density-adapted cooperative CAR targeting to selectively eliminate AML and potentially obviate the need for hematopoietic rescue. Competing Interests: 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. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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