Tadalafil has biologic activity in human melanoma. Results of a pilot trial with Tadalafil in patients with metastatic Melanoma (TaMe).
Tadalafil has biologic activity in human melanoma. Results of a pilot trial with Tadalafil in patients with metastatic Melanoma (TaMe).
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DOI：
10.1080/2162402x.2017.1326440
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发表时间：
2017
期刊：
影响因子：
7.2
通讯作者：
Umansky V
中科院分区：
文献类型：
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作者：
Hassel JC;Jiang H;Bender C;Winkler J;Sevko A;Shevchenko I;Halama N;Dimitrakopoulou-Strauss A;Haefeli WE;Jäger D;Enk A;Utikal J;Umansky V
骨髓源性抑制细胞（MDSC）在抑制T细胞抗肿瘤反应中起关键作用。我们的临床前数据显示，磷酸二酯酶（PDE）-5抑制剂西地那非损害MDSC功能，增强肿瘤内T细胞活性，延长荷黑色素瘤小鼠的生存期。在这项研究中，我们评估了PDE-5抑制剂他达拉非在转移性黑色素瘤患者中姑息治疗的生物学效应、安全性和有效性。我们在预先治疗的转移性黑色素瘤患者中进行了一项他达拉非的开放标签、剂量递减试验。在治疗开始前和治疗开始后4周采集肿瘤和外周血样品。通过免疫组织化学和流式细胞仪分析，以CD 8+肿瘤浸润淋巴细胞（TIL）的数量作为主要终点，对不同免疫亚群的样本进行研究。3/12例患者（25%）病情稳定。中位无进展生存期为4.6个月（范围0.7-7.1），中位总生存期（OS）为8.5个月（范围2.7-23.7）。治疗耐受性良好。与进展患者相比，稳定患者在治疗前转移中心显示出显著更高的CD 8 + TIL数量。在治疗后，与基线相比，他们显示出外周血中CD 8+和CD 4 + TIL以及CD 8 +T细胞中β-链（用作T细胞活化的标志物）的表达增加。我们的研究表明，PDE-5抑制剂他达拉非可以通过增强抗肿瘤免疫来改善晚期黑色素瘤患者的临床结局，并突出了其在联合黑色素瘤免疫治疗中的潜在应用。
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.