High-avidity cathepsin-G–specific CAR T cells for the treatment of acute myeloid leukemia
ABSTRACT: Chimeric antigen receptor (CAR) T cells specific for myeloid-associated antigens expressed on the cell surface of acute myeloid leukemia (AML) can cause depletion of normal myeloid progenitor cells. We developed a CAR specific for an HLA-A∗02:01-restricted peptide of the myeloid-restricted cathepsin-G (CG) protein. CG-specific CAR T cells (CG1.CAR) were further engineered to increase their functional avidity. Specifically, we developed CG1.CAR T cells coexpressing the lymphocyte-specific protein tyrosine kinase (LCK) and duplicated CD3ζ chain, which allows the functional recognition of the CG1 peptide as low as 0.025μM. Optimized CG1.CAR T cells displayed antileukemia effects in vitro and in vivo in patient-derived AML xenotransplant mouse models and did not cause hematopoietic toxicity in colony assays and humanized mice. Mechanistically, LCK overexpression in CG1.CAR T cells caused transcriptional modifications characterized by the overexpression of mitochondrial-encoded electron transport chain components that were correlated with increased mitochondrial mass and improved respiratory capacity. Based on these data, CG1.CAR T cells hold clinical potential for the treatment of AML.
Authors
- Marta Serafini (ORCID: https://orcid.org/0000-0001-8105-6476)
- Tracy Withers
- Elizabeth G. Hunt (ORCID: https://orcid.org/0000-0002-5721-3336)
- Andrew S. Kennedy (ORCID: https://orcid.org/0000-0002-9866-7190)
- Eben I. Lichtman (ORCID: https://orcid.org/0000-0002-5166-8938)
- Ziyou Cui (ORCID: https://orcid.org/0000-0002-4002-2509)
- Marta Biondi (ORCID: https://orcid.org/0000-0003-1156-2255)
- Cheng Liu (ORCID: https://orcid.org/0000-0002-7419-8529)
- Ourania Tsahouridis (ORCID: https://orcid.org/0000-0003-0621-6753)
- Mark G. Woodcock (ORCID: https://orcid.org/0000-0001-7348-4980)
- Peishun Shou (ORCID: https://orcid.org/0000-0001-7685-7471)
- Simone Stucchi (ORCID: https://orcid.org/0000-0003-3315-9205)
- Paul M. Armistead (ORCID: https://orcid.org/0000-0003-3983-5534)
- Lishan Su (ORCID: https://orcid.org/0000-0002-0350-5560)
- Jessica E. Thaxton (ORCID: https://orcid.org/0000-0003-1759-5576)
- Guangming Li (ORCID: https://orcid.org/0000-0003-2076-609X)
- Guangyan Xiong
- Tara Walhart (ORCID: https://orcid.org/0000-0002-1176-3973)
- Feifei Song (ORCID: https://orcid.org/0000-0002-8866-1270)
- Kyogo Suzuki (ORCID: https://orcid.org/0000-0001-8643-2987)
- Leah Flick
- Barbara Savoldo
- Laura E. Herring
- Pei Wang (ORCID: https://orcid.org/0009-0005-8499-0893)
- Zhiyuan Yang
- Courtney G. Elliott
- Sally A. Hunsucker
- Gianpietro Dotti
Institutions
- University of North Carolina at Chapel Hill (US)
- University of Maryland, Baltimore (US)
- Eureka Therapeutics (United States) (US)
- Institute of Human Virology (NG)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University of Milano-Bicocca (IT)
Publication Details
- Journal
- Blood
- Published
- 2026-08-20
- DOI
- https://doi.org/10.1182/blood.2025030577
- Citations
- 1
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 4.34