{"doi":"10.1172/jci133215","title":"Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability","abstract":"Chimeric antigen receptor-T (CAR-T) cell therapies can eliminate relapsed and refractory tumors, but the durability of antitumor activity requires in vivo persistence. Differential signaling through the CAR costimulatory domain can alter the T cell metabolism, memory differentiation, and influence long-term persistence. CAR-T cells costimulated with 4-1BB or ICOS persist in xenograft models but those constructed with CD28 exhibit rapid clearance. Here, we show that a single amino acid residue in CD28 drove T cell exhaustion and hindered the persistence of CD28-based CAR-T cells and changing this asparagine to phenylalanine (CD28-YMFM) promoted durable antitumor control. In addition, CD28-YMFM CAR-T cells exhibited reduced T cell differentiation and exhaustion as well as increased skewing toward Th17 cells. Reciprocal modification of ICOS-containing CAR-T cells abolished in vivo persistence and antitumor activity. This finding suggests modifications to the costimulatory domains of CAR-T cells can enable longer persistence and thereby improve antitumor response.","journal":"Journal of Clinical Investigation","year":2020,"id":50343,"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":197,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9465,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":247162,"name":"Aviv Madar","orcid":"0000-0003-2282-8848","position":1,"is_corresponding":false},{"id":247163,"name":"Victoria Casado‐Medrano","orcid":"0000-0002-6929-4559","position":2,"is_corresponding":false},{"id":248717,"name":"Carolyn E. Shaw","orcid":null,"position":3,"is_corresponding":false},{"id":248718,"name":"Anna Wing","orcid":null,"position":4,"is_corresponding":false},{"id":227864,"name":"Fang Liu","orcid":"0000-0003-2922-4414","position":5,"is_corresponding":false},{"id":247164,"name":"Regina M. Young","orcid":"0000-0002-0158-9449","position":6,"is_corresponding":false},{"id":227870,"name":"Carl H. June","orcid":"0000-0003-0241-3557","position":7,"is_corresponding":false},{"id":227871,"name":"Avery D. Posey","orcid":"0000-0001-8711-629X","position":8,"is_corresponding":false},{"id":248716,"name":"Sònia Guedan","orcid":null,"position":0,"is_corresponding":true}],"reference_count":78,"raw_metadata":null,"created_at":"2026-07-18T20:38:25.860949Z","pmid":"32069268","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":[]}