High-avidity cathepsin-G–specific CAR T cells for the treatment of acute myeloid leukemia
Tara Walhart, Marta Biondi, Simone Stucchi, Guangming Li, Ourania Tsahouridis, Peishun Shou, Kyogo Suzuki, Elizabeth G. Hunt, Andrew Kennedy, Jessica E. Thaxton, Tracy Withers, Laura E. Herring, Courtney G. Elliott, Sally A. Hunsucker, Marta Serafini, Leah Flick, Eben I. Lichtman, Mark Woodcock, Lishan Su, Zhiyuan Yang, Guangyan Xiong, Ziyou Cui, Pei Wang, Cheng Liu, Barbara Savoldo, Paul M. Armistead, Feifei Song, Gianpietro DottiAbstract
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.