Tadalafil has biologic activity in human melanoma. Results of a pilot trial with Tadalafil in patients with metastatic Melanoma (TaMe)

Myeloid-derived suppressor cells (MDSCs) are known to play a critical role in the suppression of T cell antitumor responses. Our preclinical data showed that the phosphodiesterase (PDE)-5 inhibitor sildenafil impaired MDSC functions, enhanced intratumoral T cell activity and prolonged survival of melanoma-bearing mice. In this study, we evaluated biologic effects, safety and efficacy of palliative treatment with the PDE-5 inhibitor tadalafil in metastatic melanoma patients. We conducted an open-label, dose de-escalation trial with tadalafil in pretreated metastatic melanoma patients. Tumor and peripheral blood samples were taken before and 4weeks after the start of treatment. Samples were investigated by immunohistochemistry and FACS analysis, for different immune subsets with numbers of CD8(+) tumor-infiltrating lymphocytes (TIL) as primary end point. Stable disease was achieved in 3/12 patients (25%). Median progression-free survival was 4.6mo (range 0.7-7.1), median overall survival (OS) 8.5mo (range 2.7-23.7). The treatment was well tolerated. Stable patients displayed significantly higher numbers of CD8(+) TIL in the center of metastases before treatment as compared with progressive patients. Upon the therapy, they showed increased expression of -chain (used as a marker of T cell activation) in CD8(+) and CD4(+)TILs and CD8(+)T cells in the peripheral blood as compared with baseline. Our study suggests that the PDE-5 inhibitor tadalafil can improve clinical outcome of advanced melanoma patients by enhancing antitumor immunity and highlights its potential application in combined melanoma immunotherapy.