Granulocyte/macrophage-colony-stimulating-factor plus interleukin-2 plus interferon alpha in the treatment of metastatic renal cell carcinoma: a pilot study.
Granulocyte/macrophage-colony-stimulating factor (GM-CSF) plays a central role in the differentiation and function of dendritic cells, which are crucial for the elicitation of MHC-restricted T cell responses. Preclinical and the first clinical data provide a rationale for the application of GM-CSF in immunotherapy of cancer. Ten patients with renal cell carcinoma stage IV (Holland/ Robson) were treated in this pilot study. Therapy was started with GM-CSF alone (2 weeks). Interleukin (IL-2) and interferon alpha (IFNalpha) were added sequentially (3 weeks GM-CSF plus IL-2 or IFNalpha, 3 weeks GM-CSF plus IL-2 plus IFNalpha). Therapy was performed on an outpatient basis. The cytokine regimen was evaluated for toxicity, clinical response and immunomodulatory effects [fluorescence-activated cell sorting analysis of peripheral blood mononuclear cells (PBMC), mixed-lymphocyte reaction and cytotoxicity of PBMC]. GM-CSF treatment caused a significant increase in the number of PBMC expressing costimulatory molecules. Addition of IL-2 and IFNalpha led to an increase in CD3 , CD4+, CD8+ and CD56+ PBMC in week 9. In an autologous mixed-lymphocyte reaction a 2.1-fold increase in T cell proliferation was observed after 2 weeks of GM-CSF treatment, and cytotoxicity assays showed changes in natural-killer-(NK)- and non-NK-mediated cytotoxicity in some patients. Two patients achieved partial remission, one patient had a mixed response. The toxicity of the regimen was mild to moderate with fever, flu-like symptoms and nausea being observed in most patients. Severe organ toxicity was not observed. We conclude that GM-CSF might be useful for immunotherapy of renal cell carcinoma, especially in combination with T-cell-active cytokines. Further studies are warranted.
Westermann
J
J
Department of Hematology, Oncology and Tumorimmunology, Robert Rössle Clinic, Charite, Humboldt University, Berlin, Germany.
Reich
G
G
Kopp
J
J
Haus
U
U
Dörken
B
B
Pezzutto
A
A
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D004334:Drug Administration Schedule; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology; D007958:Leukocyte Count; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D016131:Lymphocyte Subsets / Q000145:classification; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D010865:Pilot Projects; D014407:Tumor Cells, Cultured
D016898:Interferon-alpha; D007376:Interleukin-2; D016178:Granulocyte-Macrophage Colony-Stimulating Factor