Tadalafil has biologic activity in human melanoma

• Verfasst von: Hassel, Jessica C. [VerfasserIn]
• Verfasst von: Bender, Carolin [VerfasserIn]
• Verfasst von: Winkler, Julia K. [VerfasserIn]
• Verfasst von: Halama, Niels [VerfasserIn]
• Verfasst von: Dimitrakopoulou-Strauss, Antonia [VerfasserIn]
• Verfasst von: Haefeli, Walter E. [VerfasserIn]
• Verfasst von: Jäger, Dirk [VerfasserIn]
• Verfasst von: Enk, Alexander [VerfasserIn]
• Verfasst von: Utikal, Jochen [VerfasserIn]
• Verfasst von: Umansky, Viktor [VerfasserIn]
• Titel: Tadalafil has biologic activity in human melanoma
• Titelzusatz: results of a pilot trial with Tadalafil in patients with metastatic Melanoma (TaMe)
• Verf.angabe: Jessica C. Hassel, Huanhuan Jiang, Carolin Bender, Julia Winkler, Alexandra Sevko, Ivan Shevchenko, Niels Halama, Antonia Dimitrakopoulou-Strauss, Walter E. Haefeli, Dirk Jäger, Alexander Enk, Jochen Utikal, and Viktor Umansky
• E-Jahr: 2017
• Jahr: 24 Aug 2017
• Umfang: 10 S.
• Fussnoten: Gesehen am 18.04.2018
• Titel Quelle: Enthalten in: OncoImmunology
• Ort Quelle: Abingdon : Taylor & Franics, 2012
• Jahr Quelle: 2017
• Band/Heft Quelle: 6(2017) Artikel-Nummer e1326440, 10 Seiten
• ISSN Quelle: 2162-402X
• DOI: doi:10.1080/2162402X.2017.1326440
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Immunotherapy
• Sach-SW: melanoma
• Sach-SW: myeloid suppressor cells
• Sach-SW: phosphodiesterase-5 inhibitor
• Sach-SW: tadalafil
• K10plus-PPN: 1572119780

Abstract

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 4 weeks 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 4.6 mo (range 0.7-7.1), median overall survival (OS) 8.5 mo (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 ζ-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.