title: Phase I trial of combined immunotherapy with subcutaneous granulocyte macrophage colony-stimulating factor, low-dose interleukin 2, and interferon alpha in progressive metastatic melanoma and renal cell carcinoma.
abstract: The purpose of our study was to determine the maximally tolerated dose (MTD) and DLT of combined administration of granulocyte macrophage colony-stimulating factor (GM-CSF), low-dose interleukin 2 (IL-2) and IFN-alpha in patients with progressive metastatic melanoma or renal cell carcinoma (RCC). In addition, the activation and expansion of effector cells were measured. Cohorts of three patients were treated with increasing doses of IL-2 (1, 4, and 8 MIU/m2) and GM-CSF (2.5 and 5 microg/kg) with a constant dose of IFNalpha (5 million units) s.c. for 12 days every 3 weeks. An additional six patients were treated at the MTD. Immune activation was monitored during the first cycle. Response was evaluated after two cycles. The MTD was found to be 2.5 microg/kg GM-CSF, 4 MIU/m2 IL-2, and 5 mega units of IFNalpha. DLT was grade 4 fever, chills with hypotension, grade 3 fatigue/malaise, and fluid retention. Dose reduction of IL-2 to 2 MIU/m2 was necessary in three of nine patients who initially received the MTD. Treatment was initiated in the hospital but could be continued at home after 3-4 days. Significant increases in lymphocytes, (activated) T cells (CD4+ and CD8+), NK cells, monocyte DR expression, neutrophils, and eosinophils were found. CD8+ T-cell activation (sCD8) and NK cell expansion was mainly present in patients receiving 2 or 4 MIU/m2 IL-2. Of eight patients with progressive metastatic RCC after nephrectomy, three achieved a complete remission, and 1 of 7 patients with metastatic melanoma achieved a partial remission. In our study, the MTD of combined immunotherapy with GM-CSF, IL-2, and IFNalpha was established; DLT was: (a) grade 4 fever with hypotension needing i.v. fluid support; and (b) grade 3 fluid retention and/or fatigue/malaise. The scheme resulted in considerable expansion and/or activation of various effector cells. The complete responses in RCC patients are promising but need to be confirmed in Phase II studies.
authors.affiliation: Division of Medical Oncology, Antoni van Leeuwenhoek Hospital/Netherlands Cancer Institute, Amsterdam. irene@nki.nl
authors.forename: G C
authors.initials: GC
authors.lastname: de Gast
authors.forename: H J
authors.initials: HJ
authors.lastname: Klümpen
authors.forename: F A
authors.initials: FA
authors.lastname: Vyth-Dreese
authors.forename: M J
authors.initials: MJ
authors.lastname: Kersten
authors.forename: N C
authors.initials: NC
authors.lastname: Verra
authors.forename: J
authors.initials: J
authors.lastname: Sein
authors.forename: D
authors.initials: D
authors.lastname: Batchelor
authors.forename: W J
authors.initials: WJ
authors.lastname: Nooijen
authors.forename: J H
authors.initials: JH
authors.lastname: Schornagel
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016827:CD8 Antigens / Q000097:blood / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005334:Fever / Q000139:chemically induced; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007167:Immunotherapy; D007279:Injections, Subcutaneous; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018655:Lymphocyte Count / Q000187:drug effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D015375:Receptors, Interleukin-2 / Q000097:blood / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome; D015430:Weight Gain / Q000187:drug effects
chemical_list: D016827:CD8 Antigens; D016207:Cytokines; D016898:Interferon-alpha; D007376:Interleukin-2; D015375:Receptors, Interleukin-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor