{"doi":"10.1172/jci178558","title":"IL-2–inducible T cell kinase deficiency sustains chimeric antigen receptor T cell therapy against tumor cells","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.","journal":"Journal of Clinical Investigation","year":2024,"id":434501,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9536,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1241243,"name":"Zineng Huang","orcid":"0000-0003-3520-1702","position":1,"is_corresponding":false},{"id":1214932,"name":"Hao Xu","orcid":"0000-0001-6499-8701","position":2,"is_corresponding":false},{"id":1241779,"name":"Qingbai Liu","orcid":null,"position":3,"is_corresponding":false},{"id":1241244,"name":"Jing Li","orcid":"0000-0002-1294-4020","position":4,"is_corresponding":false},{"id":1241780,"name":"Keqing Song","orcid":null,"position":5,"is_corresponding":false},{"id":1241781,"name":"Yating Deng","orcid":null,"position":6,"is_corresponding":false},{"id":1241782,"name":"Yujia Tao","orcid":null,"position":7,"is_corresponding":false},{"id":1241245,"name":"Huifang Zhang","orcid":"0000-0002-3713-6951","position":8,"is_corresponding":false},{"id":58166,"name":"Peilong Wang","orcid":"0000-0003-2309-9982","position":9,"is_corresponding":false},{"id":497773,"name":"Heng Li","orcid":"0000-0002-6666-0277","position":10,"is_corresponding":false},{"id":1241246,"name":"Sheng Yue","orcid":"0009-0005-4973-6136","position":11,"is_corresponding":false},{"id":1241247,"name":"Aijun Zhou","orcid":"0000-0002-6404-0082","position":12,"is_corresponding":false},{"id":1241783,"name":"Lianbin Han","orcid":null,"position":13,"is_corresponding":false},{"id":1241248,"name":"Yan Fu","orcid":"0000-0002-4942-159X","position":14,"is_corresponding":false},{"id":138364,"name":"C Wang","orcid":null,"position":15,"is_corresponding":false},{"id":609179,"name":"Saurav Kumar Choudhary","orcid":null,"position":16,"is_corresponding":false},{"id":361139,"name":"Kaixiong Ye","orcid":"0000-0003-4658-7292","position":17,"is_corresponding":false},{"id":419724,"name":"Gianluca Veggiani","orcid":"0000-0002-4064-0112","position":18,"is_corresponding":false},{"id":1241249,"name":"Zhihong Li","orcid":"0000-0003-4412-6038","position":19,"is_corresponding":false},{"id":302240,"name":"Avery August","orcid":"0000-0003-4968-3415","position":20,"is_corresponding":false},{"id":302237,"name":"Weishan Huang","orcid":"0000-0002-1330-1131","position":21,"is_corresponding":false},{"id":1241250,"name":"Qiang Shan","orcid":"0000-0002-7717-2922","position":22,"is_corresponding":false},{"id":1667,"name":"Hongling Peng","orcid":"0000-0003-2770-5150","position":23,"is_corresponding":false},{"id":291515,"name":"Zheng Fu","orcid":"0000-0003-0837-3728","position":0,"is_corresponding":true}],"reference_count":71,"raw_metadata":null,"created_at":"2026-07-19T01:59:58.582186Z","pmid":"39589809","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}