C-JUN overexpressing CAR-T cells in acute myeloid leukemia: preclinical characterization and phase I trial

Shiyu Zuo, Chuo Li, Xiaolei Sun, Biping Deng, Yibing Zhang, Yajing Han, Zhuojun Ling, Jinlong Xu, Jiajia Duan, Zelin Wang, Xinjian Yu, Qinlong Zheng, Xiuwen Xu, Jiao Zong, Zhenglong Tian, Lingling Shan, Kaiting Tang, Huifang Huang, Yanzhi Song, Qing Niu, Dongming Zhou, Sizhou Feng, Zhongchao Han, Guoling Wang (), Tong Wu (), Jing Pan () and Xiaoming Feng ()
Additional contact information
Shiyu Zuo: Chinese Academy of Medical Sciences & Peking Union Medical College
Chuo Li: Chinese Academy of Medical Sciences & Peking Union Medical College
Xiaolei Sun: Chinese Academy of Medical Sciences & Peking Union Medical College
Biping Deng: Beijing GoBroad Boren Hospital
Yibing Zhang: Chinese Academy of Medical Sciences & Peking Union Medical College
Yajing Han: Chinese Academy of Medical Sciences & Peking Union Medical College
Zhuojun Ling: Beijing GoBroad Boren Hospital
Jinlong Xu: Beijing GoBroad Boren Hospital
Jiajia Duan: Beijing GoBroad Boren Hospital
Zelin Wang: Beijing GoBroad Boren Hospital
Xinjian Yu: Beijing GoBroad Boren Hospital
Qinlong Zheng: Beijing GoBroad Boren Hospital
Xiuwen Xu: Beijing GoBroad Boren Hospital
Jiao Zong: Beijing GoBroad Boren Hospital
Zhenglong Tian: Gobroad Medical Group
Lingling Shan: Chinese Academy of Medical Sciences & Peking Union Medical College
Kaiting Tang: Chinese Academy of Medical Sciences & Peking Union Medical College
Huifang Huang: Fujian Medical University Union Hospital
Yanzhi Song: Beijing GoBroad Boren Hospital
Qing Niu: Chinese Academy of Medical Sciences & Peking Union Medical College
Dongming Zhou: Tianjin Medical University
Sizhou Feng: Chinese Academy of Medical Sciences & Peking Union Medical College
Zhongchao Han: Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd
Guoling Wang: Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center
Tong Wu: Beijing GoBroad Boren Hospital
Jing Pan: Beijing GoBroad Boren Hospital
Xiaoming Feng: Chinese Academy of Medical Sciences & Peking Union Medical College

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Chimeric antigen receptor (CAR) T cells show suboptimal efficacy in acute myeloid leukemia (AML). We find that CAR T cells exposed to myeloid leukemia show impaired activation and cytolytic function, accompanied by impaired antigen receptor downstream calcium, ZAP70, ERK, and C-JUN signaling, compared to those exposed to B-cell leukemia. These defects are caused in part by the high expression of CD155 by AML. Overexpressing C-JUN, but not other antigen receptor downstream components, maximally restores anti-tumor function. C-JUN overexpression increases costimulatory molecules and cytokines through reinvigoration of ERK or transcriptional activation, independent of anti-exhaustion. We conduct an open-label, non-randomized, single-arm, phase I trial of C-JUN-overexpressing CAR-T in AML (NCT04835519) with safety and efficacy as primary and secondary endpoints, respectively. Of the four patients treated, one has grade 4 (dose-limiting toxicity) and three have grade 1–2 cytokine release syndrome. Two patients have no detectable bone marrow blasts and one patient has blast reduction after treatment. Thus, overexpressing C-JUN endows CAR-T efficacy in AML.

Date: 2024
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DOI: 10.1038/s41467-024-50485-9

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