IL-2-inducible T cell kinase deficiency sustains chimeric antigen receptor T cell therapy against tumor cells

Authors

• Zheng Fu, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
• Zineng Huang, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
• Hao Xu, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu, China
• Qingbai Liu, Nanjing Medical University, Huai'an, Jiangsu Province, China
• Jing Li, Beijing Institute of Technology School of Chemistry and Chemical Engineering, Beijing, China
• Keqing Song, Tianjin Mogenetics Biotech Co. Ltd., Tianjin, China
• Yating Deng, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
• Yujia Tao, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
• Huifang Zhang, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
• Peilong Wang, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
• Heng Li, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
• Yue Sheng, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
• Aijun Zhou, Nanjing Medical University, Huai'an, Jiangsu Province, China
• Lianbin Han, MegaRobo Technologies Co. Ltd., Suzhou, China
• Yan Fu, MegaRobo Technologies Co. Ltd., Suzhou, China
• Chenzhi Wang, MegaRobo Technologies Co. Ltd., Suzhou, China
• Saurav Kumar Choudhary, University of Georgia, Athens, GA
• Kaixiong Ye, University of Georgia, Athens, GA
• Gianluca Veggiani, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA
• Zhihong Li, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
• Avery August, Cornell University, Ithaca, NY
• Weishan Huang, Louisiana State University School of Veterinary Medicine, Baton Rouge, LA
• Qiang Shan, Chinese Academy of Medical Sciences & Peking Union Medical College, Suzhou, Jiangsu, China
• Hongling Peng, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China

Document Type

Article

Publication Date

11-26-2024

Publication Title

The Journal of Clinical Investigation

Abstract

Despite the revolutionary achievements of chimeric antigen receptor (CAR) T cell therapy in treating cancers, especially leukemia, several key challenges still limit its therapeutic efficacy. Of particular relevance is the relapse of cancer in large part as a result of exhaustion and short persistence of CAR-T cells in vivo. IL-2-inducible T cell kinase (ITK) is a critical modulator of the strength of T cell receptor signaling, while its role in CAR signaling is unknown. By electroporation of CRISPR-associated protein 9 (Cas9) ribonucleoprotein (RNP) complex into CAR-T cells, we successfully deleted ITK in CD19-CAR-T cells with high efficiency. Bulk and single-cell RNA sequencing analyses revealed downregulation of exhaustion and upregulation of memory gene signatures in ITK-deficient CD19-CAR-T cells. Our results further demonstrated a significant reduction of T cell exhaustion and enhancement of T cell memory, with significant improvement of CAR-T cell expansion and persistence both in vitro and in vivo. Moreover, ITK-deficient CD19-CAR-T cells showed better control of tumor relapse. Our work provides a promising strategy of targeting ITK to develop sustainable CAR-T cell products for clinical use.

First Page

1

Last Page

16

DOI

10.1172/JCI178558

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Fu, Zheng; Huang, Zineng; Xu, Hao; Liu, Qingbai; Li, Jing; Song, Keqing; Deng, Yating; Tao, Yujia; Zhang, Huifang; Wang, Peilong; Li, Heng; Sheng, Yue; Zhou, Aijun; Han, Lianbin; Fu, Yan; Wang, Chenzhi; Choudhary, Saurav Kumar; Ye, Kaixiong; Veggiani, Gianluca; Li, Zhihong; August, Avery; Huang, Weishan; Shan, Qiang; and Peng, Hongling, "IL-2-inducible T cell kinase deficiency sustains chimeric antigen receptor T cell therapy against tumor cells" (2024). LSU-LCMC Cancer Center Faculty Publications. 200.
https://digitalscholar.lsuhsc.edu/llcc_facpubs/200
10.1172/JCI178558