Schilling B, Sondermann W, Zhao F, Griewank K G, Livingstone E, Sucker A, Zelba H, Weide B, Trefzer U, Wilhelm T, Loquai C, Berking C, Hassel J, Kähler K C, Utikal J, Al Ghazal P, Gutzmer R, Goldinger S M, Zimmer L, Paschen A, Hillen U, Schadendorf D
Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; German Cancer Consortium (DKTK).
Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen; German Cancer Consortium (DKTK).
Ann Oncol. 2014 Mar;25(3):747-753. doi: 10.1093/annonc/mdt587. Epub 2014 Feb 6.
Since the majority of melanomas eventually become resistant and progress, combining selective BRAF inhibitors (BRAFi) with immunotherapies has been proposed to achieve more durable treatment responses. Here, we explored the impact of selective BRAFi on the hosts' immune system.
Clinical data, whole blood counts (WBC) and serum lactate dehydrogenase (LDH) of 277 vemurafenib- and 65 dabrafenib-treated melanoma patients were evaluated. The frequency and phenotype of lymphocyte subpopulations were determined by flow cytometry while T cell cytokine secretion was measured by multiplex assays.
Progression-free survival (PFS) as well as overall survival (OS) were similar in patients treated with either BRAFi. High pretreatment LDH was associated with shorter PFS and OS in both groups. During therapy, peripheral lymphocytes decreased by 24.3% (median, P < 0.0001) in vemurafenib-treated patients but remained unchanged in dabrafenib-treated patients (+1.2%, P = 0.717). Differentiation of peripheral lymphocytes of vemurafenib-treated patients showed a significant decrease in CD4(+) T cells (P < 0.05). Within CD4(+) T cells obtained during treatment, an increase in CCR7(+)CD45RA(+) (naïve) and a decrease in CCR7(+)CD45RA(-) (central memory) populations were found (P < 0.01 for both). Furthermore, secretion of interferon-γ and interleukin-9 by CD4(+) T cells was significantly lower in samples obtained during vemurafenib treatment compared with baseline samples.
While both compounds have comparable clinical efficacy, vemurafenib but not dabrafenib decreases patients peripheral lymphocyte counts and alters CD4(+) T cell phenotype and function. Thus, selective BRAFi can significantly affect patients' peripheral lymphocyte populations. Fully understanding these effects could be critical for successfully implementing combinatorial therapies of BRAFi with immunomodulatory agents.
由于大多数黑色素瘤最终会产生耐药性并进展，因此有人提出将选择性BRAF抑制剂（BRAFi）与免疫疗法联合使用，以获得更持久的治疗反应。在此，我们探讨了选择性BRAFi对宿主免疫系统的影响。
评估了277例接受维莫非尼治疗和65例接受达拉非尼治疗的黑色素瘤患者的临床数据、全血细胞计数（WBC）和血清乳酸脱氢酶（LDH）。通过流式细胞术确定淋巴细胞亚群的频率和表型，同时通过多重检测测定T细胞细胞因子分泌。
接受任一BRAFi治疗的患者的无进展生存期（PFS）和总生存期（OS）相似。两组患者治疗前LDH水平高均与较短的PFS和OS相关。治疗期间，维莫非尼治疗的患者外周淋巴细胞减少了24.3%（中位数，P<0.0001），而达拉非尼治疗的患者外周淋巴细胞保持不变（增加1.2%，P=0.717）。维莫非尼治疗患者外周淋巴细胞分化显示CD4(+)T细胞显著减少（P<0.05）。在治疗期间获得的CD4(+)T细胞中，发现CCR7(+)CD45RA(+)（幼稚）细胞群增加，CCR7(+)CD45RA(-)（中央记忆）细胞群减少（两者P<0.01）。此外，与基线样本相比，维莫非尼治疗期间获得的样本中CD4(+)T细胞分泌的干扰素-γ和白细胞介素-9显著降低。
虽然两种化合物具有相当的临床疗效，但维莫非尼而非达拉非尼会降低患者外周淋巴细胞计数，并改变CD4(+)T细胞表型和功能。因此，选择性BRAFi可显著影响患者外周淋巴细胞群。充分了解这些效应对于成功实施BRAFi与免疫调节剂的联合治疗可能至关重要。
