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 r ole in the differentiation and function of dendritic cells, which are cruci al for the elicitation of MHC-restricted T cell responses. Preclinical and the first clinical data provide a rationale for the application of GM-CSF i n immunotherapy of cancer. Ten patients with renal cell carcinoma stage IV (Holland/ Robson) were treated in this pilot study. Therapy was started wit h GM-CSF alone (2 weeks). Interleukin (IL-2) and interferon alpha (IFN alph a) were added sequentially (3 weeks GM-CSF plus IL-2 or IFN alpha, 3 weeks GM-CSF plus IL-2 plus IFN alpha). Therapy was performed on an outpatient ba sis. 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 cy totoxicity of PBMC]. GM-CSF treatment caused a significant increase in the number of PBMC expressing costimulatory molecules. Addition of IL-2 and IFN alpha led to an increase in CD3(+), CD4(+), CD8(+) and CD56(+) PBMC in wee k 9. In an autologous mixed-lymphocyte reaction a 2.1-fold increase in T ce ll proliferation was observed after 2 weeks of GM-CSF treatment, and cytoto xicity assays showed changes in natural-killer(NK)- and non-NK-mediated cyt otoxicity in some patients. Two patients achieved partial remission, one pa tient had a mixed response. The toxicity of the regimen was mild to moderat e 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 u seful for immunotherapy of renal cell carcinoma, especially in combination with T-cell-active cytokines. Further studies are warranted.