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

The purpose of our study was to determine the maximally tolerated dose (MTD ) and DLT of combined administration of granulocyte macrophage colony-stimu lating factor (GM-CSF), low-dose interleukin 2 (IL-2) and IFN-or in patient s with progressive metastatic melanoma or renal cell carcinoma (RCC). In ad dition, the activation and expansion of effector cells were measured. Cohor ts of three patients were treated with increasing doses of IL-2 (1, 4, and 8 MIU/m(2)) and GM-CSF (2.5 and 5 mu g/kg) with a constant dose of IFN alph a (5 million units) s.c. for 12 days every 3 weeks. An additional six patie nts mere treated at the MTD. Immune activation was monitored during the fir st cycle. Response was evaluated after two cycles. The MTD was found to be 2.5 mu g/kg GR I-CSF, 4 MIU/m(2) IL-2, and 5 mega units of IFNa. DLT was gr ade 4 fever, chills with hypotension, grade 3 fatigue/malaise, and fluid re tention. Dose reduction of IL-2 to 2 MIU/m(2) was necessary in three of nin e patients who initially received the MTD. Treatment was initiated in the h ospital but could be continued at home after 3-4 days. Significant increase s in lymphocytes, (activated) T cells (CD4+ and CD8+), NK cells, monocyte D R expression, neutrophils, and eosinophils were found. CD8+ T-cell activati on (sCD8) and NK cell expansion was mainly present in patients receiving 2 or 4 MIU/m(2) 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 GMCSF, IL-2, and IFN alpha was established; DL T 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 c onsiderable expansion and/or activation of various effector cells. The comp lete responses in RCC patients are promising but need to be confirmed in Ph ase II studies.