{"doi":"10.1172/jci.insight.146314","title":"TNF blockade uncouples toxicity from antitumor efficacy induced with CD40 chemoimmunotherapy","abstract":"Agonist CD40 antibodies are under clinical development in combination with chemotherapy as an approach to prime for antitumor T cell immunity. However, treatment with anti-CD40 is commonly accompanied by both systemic cytokine release and liver transaminase elevations, which together account for the most common dose-limiting toxicities. Moreover, anti-CD40 treatment increases the potential for chemotherapy-induced hepatotoxicity. Here, we report a mechanistic link between cytokine release and hepatotoxicity induced by anti-CD40 when combined with chemotherapy and show that toxicity can be suppressed without impairing therapeutic efficacy. We demonstrate in mice and humans that anti-CD40 triggers transient hepatotoxicity marked by increased serum transaminase levels. In doing so, anti-CD40 sensitizes the liver to drug-induced toxicity. Unexpectedly, this biology is not blocked by the depletion of multiple myeloid cell subsets, including macrophages, inflammatory monocytes, and granulocytes. Transcriptional profiling of the liver after anti-CD40 revealed activation of multiple cytokine pathways including TNF and IL-6. Neutralization of TNF, but not IL-6, prevented sensitization of the liver to hepatotoxicity induced with anti-CD40 in combination with chemotherapy without impacting antitumor efficacy. Our findings reveal a clinically feasible approach to mitigate toxicity without impairing efficacy in the use of agonist CD40 antibodies for cancer immunotherapy.","journal":"JCI Insight","year":2021,"id":184449,"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":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9424,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":460789,"name":"Jesse Lee","orcid":"0000-0001-8335-5357","position":1,"is_corresponding":false},{"id":690705,"name":"Veronica M. Herrera","orcid":"0000-0003-0770-4548","position":2,"is_corresponding":false},{"id":280885,"name":"Kathleen Graham","orcid":"0000-0003-2548-2969","position":3,"is_corresponding":false},{"id":739652,"name":"Jae W. Lee","orcid":"0000-0002-0735-5707","position":4,"is_corresponding":false},{"id":253125,"name":"Austin P. Huffman","orcid":null,"position":5,"is_corresponding":false},{"id":739653,"name":"Heather Coho","orcid":"0009-0002-5053-939X","position":6,"is_corresponding":false},{"id":327397,"name":"Evan Tooker","orcid":null,"position":7,"is_corresponding":false},{"id":499369,"name":"Max I. Myers","orcid":"0009-0001-4981-8992","position":8,"is_corresponding":false},{"id":404464,"name":"Michael A. Giannone","orcid":"0000-0002-7604-1023","position":9,"is_corresponding":false},{"id":410091,"name":"Yan Li","orcid":"0000-0003-0420-4222","position":10,"is_corresponding":false},{"id":697152,"name":"Thomas H. Buckingham","orcid":null,"position":11,"is_corresponding":false},{"id":740362,"name":"Kristen B. Long","orcid":null,"position":12,"is_corresponding":false},{"id":251375,"name":"Gregory L. Beatty","orcid":"0000-0001-7165-5993","position":13,"is_corresponding":false},{"id":361576,"name":"Meredith L. Stone","orcid":"0000-0001-6087-1180","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-18T23:48:30.970730Z","pmid":"34101617","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":[]}