{"doi":"10.1016/j.ccell.2025.07.013","title":"Fc-optimized CD40 agonistic antibody elicits tertiary lymphoid structure formation and systemic antitumor immunity in metastatic cancer","abstract":"CD40 agonism enhances antitumor immunity but is limited by systemic toxicity and poor efficacy. Here, we present a phase 1 study (NCT04059588) of intratumoral (i.t.) 2141-V11, an Fc-engineered anti-CD40 agonistic antibody with enhanced binding to the inhibitory receptor FcγRIIB. Among 12 metastatic cancer patients, 2141-V11 was well tolerated without dose-limiting toxicities. Six patients experienced tumor reduction, including two complete responses in melanoma and breast cancer. 2141-V11 induced regression in injected and non-injected lesions, correlating with systemic CD8 + T cell activation and mature tertiary lymphoid structures (TLSs) in complete responders. In CD40/FcγRs humanized mice bearing orthotopic tumors, i.t. 2141-V11 promoted de novo TLS formation, facilitating i.t. CD8 + T cell effector responses independent of lymph node priming. The resulting local immune responses by 2141-V11 mediated abscopal antitumor effects and sustained immune memory. These findings demonstrate that i.t. 2141-V11 is safe and promotes immune-privileged tumor microenvironments that promote systemic and durable antitumor immunity.","journal":"Cancer Cell","year":2025,"id":509604,"datarank":0.5244761342199721,"base_score":3.4965075614664802,"endowment":3.4965075614664802,"self_citation_contribution":0.5244761342199721,"citation_network_contribution":0.0,"self_endowment_contribution":0.5244761342199721,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":32,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9415,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":277065,"name":"David A. Knorr","orcid":"0000-0002-0766-8914","position":1,"is_corresponding":false},{"id":1327020,"name":"Polina Weitzenfeld","orcid":"0000-0001-7044-115X","position":2,"is_corresponding":false},{"id":1043888,"name":"Lucas Blanchard","orcid":"0000-0001-6942-7086","position":3,"is_corresponding":false},{"id":1151262,"name":"Ning Yao","orcid":"0009-0006-9658-7142","position":4,"is_corresponding":false},{"id":1043890,"name":"Maria Baez","orcid":"0009-0005-6059-5792","position":5,"is_corresponding":false},{"id":1224337,"name":"Carlo Sevilla","orcid":null,"position":6,"is_corresponding":false},{"id":1327478,"name":"M Dilillo","orcid":null,"position":7,"is_corresponding":false},{"id":557773,"name":"Jahan Rahman","orcid":"0000-0001-8755-5890","position":8,"is_corresponding":false},{"id":572367,"name":"Ved P. Sharma","orcid":"0000-0001-9998-5070","position":9,"is_corresponding":false},{"id":403831,"name":"Jacqueline Bromberg","orcid":"0000-0002-7957-9339","position":10,"is_corresponding":false},{"id":68931,"name":"Michael A. Postow","orcid":"0000-0002-3367-7961","position":11,"is_corresponding":false},{"id":245669,"name":"Charlotte E. Ariyan","orcid":"0000-0003-0818-3895","position":12,"is_corresponding":false},{"id":90758,"name":"Mark E. Robson","orcid":"0000-0002-3109-1692","position":13,"is_corresponding":false},{"id":109914,"name":"Jeffrey V. Ravetch","orcid":"0000-0003-2024-9041","position":14,"is_corresponding":false},{"id":864613,"name":"Juan C. Osorio","orcid":"0000-0001-8090-1551","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:47:24.513904Z","pmid":"40816292","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":[]}