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 me...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
24 Aug 2017
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| In: |
OncoImmunology
Year: 2017, Volume: 6, Issue: 9 |
| ISSN: | 2162-402X |
| DOI: | 10.1080/2162402X.2017.1326440 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1080/2162402X.2017.1326440 Verlag, Volltext: https://doi.org/10.1080/2162402X.2017.1326440 
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| Author Notes: | 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 |
| Summary: | 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. |
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| Item Description: | Gesehen am 18.04.2018 |
| Physical Description: | Online Resource |
| ISSN: | 2162-402X |
| DOI: | 10.1080/2162402X.2017.1326440 |