{"doi":"10.3389/fimmu.2020.00868","title":"IL-15 in the Combination Immunotherapy of Cancer","abstract":"NK cells and a 5.8-fold increase in CD8 T cells. However, IL-15 preparations administered as monotherapy were ineffective, due to actions of immunological checkpoints and due to the lack of tumor specific targeting by NK cells. To circumvent checkpoints, trials of IL-15 in combination with other anticancer agents were initiated. Tumor-bearing mice receiving IL-15 with antibodies to CTLA-4 and PD-L1 manifested marked prolongation of survival compared to mice receiving IL-15 with either agent alone. In translation, a phase I trial was initiated involving IL-15 (rhIL-15), nivolumab and ipilimumab in patients with malignancy (NCT03388632). In rhesus macaques CIV IL-15 at 20 μg/kg/day for 10 days led to an 80-fold increase in number of circulating effector memory CD8 T cells. However, administration of γc cytokines such as IL-15 led to paralysis/depression of CD4 T-cells that was mediated through transient expression of SOCS3 that inhibited the STAT5 signaling pathway. This lost CD4 helper role could be restored alternatively by CD40 agonists. In the TRAMP-C2 prostate tumor model the combination of IL-15 with agonistic anti-CD40 produced additive effects in terms of numbers of TRAMP-C2 tumor specific Spas/SCNC/9H tetramer positive CD8 T cells expressed and tumor responses. A clinical trial is being initiated for patients with cancer using an intralesional anti-CD40 in combination with CIV rhIL-15. To translate IL-15-mediated increases in NK cells, we investigated combination therapy of IL-15 with anticancer monoclonal antibodies including rituximab in mouse models of EL-4 lymphoma transfected with human CD20 and with alemtuzumab (CAMPATH-1H) in a xenograft model of adult T cell leukemia (ATL). IL-15 enhanced the ADCC and therapeutic efficacy of both antibodies. These results provided the scientific basis for trials of IL-15 combined with alemtuzumab (anti-CD52) for patients with ATL (NCT02689453), with obinutuzumab (anti-CD20) for patients with CLL (NCT03759184), and with avelumab (anti-PD-L1) in patients with T-cell lymphoma (NCT03905135) and renal cancer (NCT04150562). In the first trial, there was elimination of circulating ATL and CLL leukemic cells in select patients.","journal":"Frontiers in Immunology","year":2020,"id":49481,"datarank":4.11896208560296,"base_score":5.537334267018537,"endowment":5.537334267018537,"self_citation_contribution":0.8306001400527806,"citation_network_contribution":3.2883619455501796,"self_endowment_contribution":0.8306001400527806,"citer_contribution":3.2883619455501796,"corpus_percentile":null,"corpus_rank":null,"citation_count":253,"citer_count":100,"citers_with_citation_signal":100,"citers_with_endowment":100,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9544,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT02689453","NCT04150562","NCT03388632","NCT03905135","NCT03759184"]},"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":238493,"name":"Sigrid Dubois","orcid":"0000-0002-4543-5222","position":1,"is_corresponding":false},{"id":238494,"name":"Miloš D. Miljković","orcid":"0000-0001-5848-6320","position":2,"is_corresponding":false},{"id":238495,"name":"Kevin C. Conlon","orcid":"0000-0002-4118-7524","position":3,"is_corresponding":false},{"id":238492,"name":"Thomas A. Waldmann","orcid":"0000-0003-4500-6660","position":0,"is_corresponding":true}],"reference_count":86,"raw_metadata":null,"created_at":"2026-07-18T20:36:25.163232Z","pmid":"32508818","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":[]}