University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, 5150 Centre Avenue (555), Pittsburgh, PA 15232 USA.
J Immunother Cancer. 2015 Sep 15;3:39. doi: 10.1186/s40425-015-0081-1. eCollection 2015.
We evaluated candidate circulating serum cytokines, chemokines and growth factors in patients with locally/regionally advanced melanoma receiving neoadjuvant ipilimumab with toxicity and clinical outcome.
Patients were treated with ipilimumab (10 mg/kg IV every 3 weeks, 2 doses) before and after surgery. xMAP multiplex serum testing for 36 functionally selected cytokines and chemokines was performed at baseline and at six weeks (following ipilimumab). Based on our prior data, the association of IL-17 and immune related colitis was tested. Serum cytokines were divided into functional groups (Th1, Th2, Regulatory, Proinflammatory) and were assessed at baseline and week 6 using sparse-group Lasso modeling to assess the association of various cytokine groups with progression free survival (PFS). The linear combination of the cytokines/chemokines in this model was then used as a risk score and a Kaplan-Meier curve was generated to examine the association of the dichotomized score and PFS.
Thirty-five patients were enrolled whose staging was: IIIB (3; N2b), IIIC (30; N2c, N3), IV (2). Median follow-up was 18 months. Among 33 evaluable patients, median PFS was 11 months (95 % CI = 6.2-19.2). IL-17 was found to correlate significantly with the incidence of grade 3 diarrhea/colitis when measured at baseline (p = 0.02) with a trend towards significance at 6 weeks (p = 0.06). In the modeling analysis, at baseline, the linear combination of 2 regulatory cytokines [TGF- β1 (ρ = 0.19) and IL-10 (ρ = -0.34)] was significantly associated with PFS (HR 2.66; p = 0.035). No significant correlations with clinical outcomes were found in examining the week 6 cytokines.
Baseline IL-17 level was significantly associated with the later development of severe diarrhea/colitis while the combination of baseline TGF- β1 and IL-10 levels were associated with therapeutic clinical outcome after neoadjuvant ipilimumab. These findings warrant further investigation and validation.
ClinicalTrials.gov Identifier NCT00972933.
我们评估了接受新辅助伊匹单抗治疗的局部/区域性晚期黑色素瘤患者的候选循环血清细胞因子、趋化因子和生长因子的毒性和临床结局。
患者在手术前后接受伊匹单抗（10mg/kg IV，每 3 周 1 次，2 剂）治疗。在基线和 6 周（伊匹单抗后）时，进行 36 种功能选择细胞因子和趋化因子的 xMAP 多重血清检测。基于我们之前的数据，测试了 IL-17 与免疫相关结肠炎的关联。将血清细胞因子分为功能组（Th1、Th2、调节性、促炎），并在基线和第 6 周使用稀疏组 Lasso 模型进行评估，以评估各种细胞因子组与无进展生存期（PFS）的相关性。该模型中细胞因子/趋化因子的线性组合随后被用作风险评分，并生成 Kaplan-Meier 曲线以检查二分评分与 PFS 的关联。
共纳入 35 例患者，分期为：IIIB（3；N2b），IIIC（30；N2c，N3），IV（2）。中位随访时间为 18 个月。在 33 例可评估患者中，中位 PFS 为 11 个月（95%CI=6.2-19.2）。在基线时，IL-17 与 3 级腹泻/结肠炎的发生率显著相关（p=0.02），在第 6 周时有显著趋势（p=0.06）。在模型分析中，在基线时，2 种调节性细胞因子[TGF-β1（ρ=0.19）和 IL-10（ρ=-0.34）]的线性组合与 PFS 显著相关（HR 2.66；p=0.035）。在检查第 6 周细胞因子时，未发现与临床结局有显著相关性。
基线 IL-17 水平与严重腹泻/结肠炎的后期发展显著相关，而基线 TGF-β1 和 IL-10 水平的组合与新辅助伊匹单抗治疗后的治疗临床结局相关。这些发现值得进一步研究和验证。
ClinicalTrials.gov 标识符 NCT00972933。
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