{"doi":"10.1136/jitc-2024-010685","title":"IL-12-producing cytokine factories induce precursor exhausted T cells and elimination of primary and metastatic tumors","abstract":"<jats:sec>\n                  <jats:title>Background</jats:title>\n                  <jats:p>Curative responses to immunotherapy require the generation of robust systemic immunity with limited toxicity. Recruitment of T cell populations such as precursor exhausted T cells (Tpex) from lymphoid tissues to tumors is a hallmark of effective treatment. However, the ability to efficiently induce this recruitment is lacking in current immunotherapy approaches. Furthermore, systemic administration of immunotherapies frequently results in dose-limiting toxicities, yielding an inadequate therapeutic window for eliciting durable responses.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Methods</jats:title>\n                  <jats:p>In this investigation, we evaluated the safety and antitumor efficacy of locally administered interleukin 12 (IL-12) using a clinically translatable cytokine delivery platform (<jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05538624\">NCT05538624</jats:ext-link>) to identify Tpex recruitment capabilities at tolerable cytokine doses.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Results</jats:title>\n                  <jats:p>We show IL-12 cytokine factories can effectively treat a broad spectrum of cancer types. Single-cell RNA sequencing data suggests that the antitumor efficacy seen in our studies was due to retinal pigmented epithelial cells-mIL12 treatment inducing differentiation of Tpex cells within the tumor microenvironment. When administered in combination with checkpoint therapy, IL-12 cytokine factory treatment generated systemic abscopal immunity, preventing subcutaneous tumor outgrowth in 8/9 mice with colorectal cancer and lung metastasis in mice with melanoma. Furthermore, this platform was well tolerated in a non-human primate without signs of toxicity.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions</jats:title>\n                  <jats:p>Our new immunotherapy approach provides a robust strategy for inducing Tpex recruitment and systemic immunity against a range of solid peritoneal malignancies, many incurable with current immunotherapy strategies. Notably, these features were achieved using IL-12, and by leveraging our technology, we avoided the toxicities that have prevented the translation of IL-12 to the clinic. Our findings provide a strong rationale for the clinical development of IL-12 cytokine factories.</jats:p>\n               </jats:sec>","journal":"Journal for ImmunoTherapy of Cancer","year":2025,"id":611131,"datarank":0.3596842909197557,"base_score":2.3978952727983707,"endowment":2.3978952727983707,"self_citation_contribution":0.3596842909197557,"citation_network_contribution":0.0,"self_endowment_contribution":0.3596842909197557,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1055284,"name":"Jonathon DeBonis","orcid":"0009-0004-8965-383X","position":1,"is_corresponding":false},{"id":1571601,"name":"Danna Murungi","orcid":null,"position":2,"is_corresponding":false},{"id":1571602,"name":"Bertha Castillo","orcid":null,"position":3,"is_corresponding":false},{"id":260088,"name":"Boram Kim","orcid":"0000-0002-2608-3778","position":4,"is_corresponding":false},{"id":640674,"name":"Fangheng Hu","orcid":"0009-0005-5886-6506","position":5,"is_corresponding":false},{"id":812354,"name":"Courtney Chambers","orcid":"0000-0002-2754-8282","position":6,"is_corresponding":false},{"id":465897,"name":"Annie Nguyen","orcid":"0000-0002-7262-271X","position":7,"is_corresponding":false},{"id":1571603,"name":"Andrea Hernandez","orcid":null,"position":8,"is_corresponding":false},{"id":1128140,"name":"Zeshi Wang","orcid":null,"position":9,"is_corresponding":false},{"id":1571604,"name":"Peter D Rios","orcid":null,"position":10,"is_corresponding":false},{"id":923053,"name":"Sofia Ghani","orcid":null,"position":11,"is_corresponding":false},{"id":1492625,"name":"Ira Joshi","orcid":"0009-0001-6313-567X","position":12,"is_corresponding":false},{"id":1502062,"name":"Douglas Isa","orcid":null,"position":13,"is_corresponding":false},{"id":978262,"name":"Ningbo Zheng","orcid":"0000-0002-3684-5596","position":14,"is_corresponding":false},{"id":254697,"name":"Weiyi Peng","orcid":"0000-0002-7785-6240","position":15,"is_corresponding":false},{"id":1571605,"name":"Oleg A Igoshin","orcid":null,"position":16,"is_corresponding":false},{"id":1571606,"name":"Jose Oberholzer","orcid":null,"position":17,"is_corresponding":false},{"id":463027,"name":"H. Courtney Hodges","orcid":"0000-0003-4441-497X","position":18,"is_corresponding":false},{"id":1571607,"name":"Nathan Reticker-Flynn","orcid":null,"position":19,"is_corresponding":false},{"id":702343,"name":"Omid Veiseh","orcid":"0000-0003-1153-8079","position":20,"is_corresponding":false},{"id":702341,"name":"Amanda Nash","orcid":"0000-0002-7704-4912","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"IL-12-producing cytokine factories induce precursor exhausted T cells and elimination of primary and metastatic tumors","abstract":"<jats:sec>\n                  <jats:title>Background</jats:title>\n                  <jats:p>Curative responses to immunotherapy require the generation of robust systemic immunity with limited toxicity. Recruitment of T cell populations such as precursor exhausted T cells (Tpex) from lymphoid tissues to tumors is a hallmark of effective treatment. However, the ability to efficiently induce this recruitment is lacking in current immunotherapy approaches. Furthermore, systemic administration of immunotherapies frequently results in dose-limiting toxicities, yielding an inadequate therapeutic window for eliciting durable responses.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Methods</jats:title>\n                  <jats:p>In this investigation, we evaluated the safety and antitumor efficacy of locally administered interleukin 12 (IL-12) using a clinically translatable cytokine delivery platform (<jats:ext-link xmlns:xlink=\"http://www.w3.org/1999/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT05538624\">NCT05538624</jats:ext-link>) to identify Tpex recruitment capabilities at tolerable cytokine doses.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Results</jats:title>\n                  <jats:p>We show IL-12 cytokine factories can effectively treat a broad spectrum of cancer types. Single-cell RNA sequencing data suggests that the antitumor efficacy seen in our studies was due to retinal pigmented epithelial cells-mIL12 treatment inducing differentiation of Tpex cells within the tumor microenvironment. When administered in combination with checkpoint therapy, IL-12 cytokine factory treatment generated systemic abscopal immunity, preventing subcutaneous tumor outgrowth in 8/9 mice with colorectal cancer and lung metastasis in mice with melanoma. Furthermore, this platform was well tolerated in a non-human primate without signs of toxicity.</jats:p>\n               </jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions</jats:title>\n                  <jats:p>Our new immunotherapy approach provides a robust strategy for inducing Tpex recruitment and systemic immunity against a range of solid peritoneal malignancies, many incurable with current immunotherapy strategies. Notably, these features were achieved using IL-12, and by leveraging our technology, we avoided the toxicities that have prevented the translation of IL-12 to the clinic. Our findings provide a strong rationale for the clinical development of IL-12 cytokine factories.</jats:p>\n               </jats:sec>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40169286","pmcid":"PMC11962782","openalex_id":null,"authors":[],"funders":[{"funder_name":"Cancer Prevention Research Institute of Texas","grant_id":"RR160047","title":null},{"funder_name":"Advanced Research Projects Agency for Health","grant_id":"AY1AX000003","title":null},{"funder_name":"Center for Cancer Research","grant_id":"R01CA272769","title":null},{"funder_name":"Common Fund","grant_id":"AI177915","title":null},{"funder_name":"NIAID NIH HHS","grant_id":"DP2 AI177915","title":null},{"funder_name":"SRA","grant_id":"","title":null}],"total_grants":6,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"gold","license":"cc-by-nc","oa_locations":[{"url":"https://jitc.bmj.com/content/13/4/e010685.full.pdf","host_type":"publisher"},{"url":"https://syndication.highwire.org/content/doi/10.1136/jitc-2024-010685","host_type":"publisher"},{"url":"https://doaj.org/article/49d9ae38b40b4685b6aadd9d4b324774","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/11962782","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC11962782","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC11962782?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":[],"mesh_terms":["Cell Line, Tumor","Animals","Humans","Mice","Neoplasms","Neoplasm Metastasis","Interleukin-12","Immunotherapy"],"keywords":["Cytokine","Gastric cancer","Colorectal Cancer","Abscopal","Immune Modulatory"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-01T15:48:31.450270Z","pmid":null,"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":[]}