title: Changes in dendritic cell phenotype after a new high-dose weekly schedule of interleukin-2 therapy for kidney cancer and melanoma.
abstract: High-dose intravenous interleukin-2 (IL-2) therapy (14 doses/course, 2 courses/cycle) for metastatic melanoma or kidney cancer induces infrequent, although major responses. In this trial, we evaluated a new schedule (dose of 600,000 IU/kg, 8 h between doses, 5 doses/course, 4 courses at weekly intervals/cycle) of high-dose IL-2, in which we inserted more planned breaks while maintaining high cumulative dose delivery, and investigated the relationship between dendritic cells (DC) and response to treatment. Target dose delivery was attained: median IL-2 cumulative dose per patient was 11.4 and 10.8 million units/kg (cycles 1 and 2, respectively). Major responses were observed in patients with kidney cancer (n=20; 3 complete and 2 partial responses) and melanoma (n=16; 1 partial response). Adverse events appeared comparable with those typically associated with high-dose IL-2. From this data set, we introduce the hypothesis-generating observation that patients who had more favorable outcomes had high pretreatment DC-to-myeloid-derived suppressor cell (MDSC) ratios, similar to the ratio observed in healthy individuals. However, even in patients with the most favorable outcome, after treatment, there were IL-2-induced changes in the DC-to-MDSC ratio, specifically increases in MDSCs. This modified IL-2 schedule is a feasible option, with a more uniform dose delivery over the treatment cycle, a similar toxicity profile, and observed complete, durable response in patients with renal cancer. Pretreatment assessment of DC phenotypic or maturational status may be a starting point to predicting response to high-dose IL-2 cytokine immunotherapy in patients with melanoma and kidney cancer.
authors.affiliation: Immunotherapy Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. steven.finkelstein@moffitt.org
authors.forename: Steven E
authors.initials: SE
authors.lastname: Finkelstein
authors.forename: Timothy
authors.initials: T
authors.lastname: Carey
authors.forename: Ingo
authors.initials: I
authors.lastname: Fricke
authors.forename: Daohai
authors.initials: D
authors.lastname: Yu
authors.forename: Dawn
authors.initials: D
authors.lastname: Goetz
authors.forename: Megan
authors.initials: M
authors.lastname: Gratz
authors.forename: Mary
authors.initials: M
authors.lastname: Dunn
authors.forename: Patricia
authors.initials: P
authors.lastname: Urbas
authors.forename: Adil
authors.initials: A
authors.lastname: Daud
authors.forename: Ronald
authors.initials: R
authors.lastname: DeConti
authors.forename: Scott
authors.initials: S
authors.lastname: Antonia
authors.forename: Dmitry
authors.initials: D
authors.lastname: Gabrilovich
authors.forename: Mayer
authors.initials: M
authors.lastname: Fishman
mesh_terms: D000328:Adult; D000368:Aged; D024221:Antineoplastic Protocols; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000009:adverse effects; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D022423:Myeloid Cells / Q000473:pathology; D009362:Neoplasm Metastasis; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D054316:Biomarkers, Pharmacological; D007376:Interleukin-2