{"doi":"10.1172/jci.insight.172728","title":"Overcoming lung cancer immunotherapy resistance by combining nontoxic variants of IL-12 and IL-2","abstract":"Engineered cytokine-based approaches for immunotherapy of cancer are poised to enter the clinic, with IL-12 being at the forefront. However, little is known about potential mechanisms of resistance to cytokine therapies. We found that orthotopic murine lung tumors were resistant to systemically delivered IL-12 fused to murine serum albumin (MSA, IL12-MSA) because of low IL-12 receptor (IL-12R) expression on tumor-reactive CD8+ T cells. IL2-MSA increased binding of IL12-MSA by tumor-reactive CD8+ T cells, and combined administration of IL12-MSA and IL2-MSA led to enhanced tumor-reactive CD8+ T cell effector differentiation, decreased numbers of tumor-infiltrating CD4+ regulatory T cells, and increased survival of lung tumor-bearing mice. Predictably, the combination of IL-2 and IL-12 at therapeutic doses led to significant dose-limiting toxicity. Administering IL-12 and IL-2 analogs with preferential binding to cells expressing Il12rb1 and CD25, respectively, led to a significant extension of survival in mice with lung tumors while abrogating dose-limiting toxicity. These findings suggest that IL-12 and IL-2 represent a rational approach to combination cytokine therapy whose dose-limiting toxicity can be overcome with engineered cytokine variants.","journal":"JCI Insight","year":2023,"id":327388,"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":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.952,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":696799,"name":"Alicia D. D’Souza","orcid":"0000-0001-7635-7573","position":1,"is_corresponding":false},{"id":511463,"name":"Maria Zagorulya","orcid":"0000-0002-4478-5378","position":2,"is_corresponding":false},{"id":1047537,"name":"Chloe V. McCreery","orcid":"0000-0001-5235-3527","position":3,"is_corresponding":false},{"id":1047538,"name":"Gita C. Abhiraman","orcid":"0000-0002-0546-4133","position":4,"is_corresponding":false},{"id":625479,"name":"Lora K. Picton","orcid":"0000-0002-0482-5187","position":5,"is_corresponding":false},{"id":877557,"name":"Allison Sheen","orcid":"0009-0008-6646-260X","position":6,"is_corresponding":false},{"id":237276,"name":"Yash Agarwal","orcid":"0000-0001-7785-7828","position":7,"is_corresponding":false},{"id":282790,"name":"Noor Momin","orcid":"0000-0003-3145-6089","position":8,"is_corresponding":false},{"id":314110,"name":"K. Dane Wittrup","orcid":"0000-0003-2398-5896","position":9,"is_corresponding":false},{"id":225709,"name":"Forest M. White","orcid":"0000-0002-1545-1651","position":10,"is_corresponding":false},{"id":218189,"name":"K. Christopher García","orcid":"0000-0001-9273-0278","position":11,"is_corresponding":false},{"id":355292,"name":"Stefani Spranger","orcid":"0000-0003-3257-4546","position":12,"is_corresponding":false},{"id":355291,"name":"Brendan Horton","orcid":"0000-0002-9551-9002","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T01:08:42.846627Z","pmid":"37669107","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":[]}