title: Immunotherapy with concurrent subcutaneous GM-CSF, low-dose IL-2 and IFN-alpha in patients with progressive metastatic renal cell carcinoma.
abstract: The purpose of the study was to determine toxicity, efficacy and immunologic effects of concurrent subcutaneous injections of low-dose interleukin-2 (LD-IL-2), granulocyte-monocyte colony-stimulating factor (GM-CSF) and interferon-alpha 2b (IFNalpha) in progressive metastatic renal cell carcinoma. In a multicentre phase II study, 59 evaluable patients received two to six cycles of subcutaneous IL-2 (4 mIU m(-2)), GM-CSF (2.5 microg kg(-1)) and IFNalpha (5 mIU flat(-1)) for 12 days per 3 weeks with evaluation after every two cycles. Cycles were repeated in responding or stable patients. Data were analysed after a median of 30 months follow-up (range 16-48 months). In 42 patients, the immunologic response was studied and related to response and survival. The main toxicity were flu-like symptoms, malaise and transient liver enzyme elevations, necessitating IL-2 reduction to 2 mIU m(-2) in 29 patients, which should be considered the maximal tolerable dose. The response was 24% (eight out of 34, three complete response (CR), five partial response (PR)) in patients with metachronic metastases and 12% (three out of 25, 2CR, 1PR) in patients with synchronic metastases. Overall response was 19% (11 out of 59). Median survival was 9.5 months. All tested patients showed expansion and/or activation of lymphocytes, T cells and subsets, NK cells, eosinophils and monocytes. Pretreatment HLA-DR levels on monocytes and number of CD4(+)HLA-DR(+) cells correlated with response. Pretreatment number of CD4(+)HLA-DR(+) cells and postimmunotherapy levels of lymphocytes, CD3(+), CD4(+) and CD8(+) T cells, but not of NK or B cells, correlated with prolonged survival. Immunotherapy with concurrent subcutaneous GM-CSF, LD-IL-2 and IFNalpha has limited toxicity, can be given as outpatient treatment and can induce durable CR. Response and survival with this form of immunotherapy seem to be more dependent on expansion/activation of T cells than of NK cells.
authors.affiliation: Division of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: Verra
authors.forename: R
authors.initials: R
authors.lastname: Jansen
authors.forename: G
authors.initials: G
authors.lastname: Groenewegen
authors.forename: H
authors.initials: H
authors.lastname: Mallo
authors.forename: M J
authors.initials: MJ
authors.lastname: Kersten
authors.forename: A
authors.initials: A
authors.lastname: Bex
authors.forename: F A
authors.initials: FA
authors.lastname: Vyth-Dreese
authors.forename: J
authors.initials: J
authors.lastname: Sein
authors.forename: W
authors.initials: W
authors.lastname: van de Kasteele
authors.forename: W J
authors.initials: WJ
authors.lastname: Nooijen
authors.forename: M
authors.initials: M
authors.lastname: de Waal
authors.forename: S
authors.initials: S
authors.lastname: Horenblas
authors.forename: G C
authors.initials: GC
authors.lastname: de Gast
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000097:blood; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000009:adverse effects / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011994:Recombinant Proteins; D016019:Survival Analysis; D013997:Time Factors
chemical_list: D015703:Antigens, CD; D000970:Antineoplastic Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007376:Interleukin-2; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor