IL-2–inducible T cell kinase deficiency sustains chimeric antigen receptor T cell therapy against tumor cells
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.
Authors
- Avery August (ORCID: https://orcid.org/0000-0003-4968-3415)
- Aijun Zhou (ORCID: https://orcid.org/0000-0002-6404-0082)
- Qiang Shan (ORCID: https://orcid.org/0000-0002-7717-2922)
- Yan Fu (ORCID: https://orcid.org/0000-0002-4942-159X)
- Gianluca Veggiani (ORCID: https://orcid.org/0000-0002-4064-0112)
- Qingbai Liu
- C Wang
- Weishan Huang (ORCID: https://orcid.org/0000-0002-1330-1131)
- Zheng Fu (ORCID: https://orcid.org/0000-0003-0837-3728)
- Zineng Huang (ORCID: https://orcid.org/0000-0003-3520-1702)
- Saurav Kumar Choudhary
- Kaixiong Ye (ORCID: https://orcid.org/0000-0003-4658-7292)
- Hao Xu (ORCID: https://orcid.org/0000-0001-6499-8701)
- Keqing Song
- Heng Li (ORCID: https://orcid.org/0000-0002-6666-0277)
- Lianbin Han
- Jing Li (ORCID: https://orcid.org/0000-0002-1294-4020)
- Peilong Wang (ORCID: https://orcid.org/0000-0003-2309-9982)
- Huifang Zhang (ORCID: https://orcid.org/0000-0002-3713-6951)
- Zhihong Li (ORCID: https://orcid.org/0000-0003-4412-6038)
- Yating Deng
- Hongling Peng (ORCID: https://orcid.org/0000-0003-2770-5150)
- Yujia Tao
- Sheng Yue (ORCID: https://orcid.org/0009-0005-4973-6136)
Institutions
- Louisiana State University (US)
- Beijing Institute of Technology (CN)
- Central South University (CN)
- University of Georgia (US)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Cornell University (US)
- Sinovac Biotech (CN)
- Mitsui Sugar (Japan) (JP)
- Suzhou Institute of Systems Medicine (CN)
- Institute of Bioinformatics (IN)
- New York State College of Veterinary Medicine (US)
- Kai Biotech (South Korea) (KR)
- Second Xiangya Hospital of Central South University (CN)
- Viva Biotech (China) (CN)
- Nanjing Medical University (CN)
- Franklin College (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-11-26
- DOI
- https://doi.org/10.1172/jci178558
- Citations
- 11
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 3.11
Funders
- Louisiana State University
- National Natural Science Foundation of China
- Central South University
- Xiamen University
- National Institutes of Health
- Xiangya Hospital, Central South University