Unit of Tumor Epigenetics, IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi, 10, 16132, Genoa, Italy.
Unit of Clinical Epidemiology, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Cancer Immunol Immunother. 2019 Jan;68(1):97-107. doi: 10.1007/s00262-018-2258-1. Epub 2018 Oct 11.
CTLA-4 blockade by means of ipilimumab (IPI) potentiates the immune response and improves overall survival (OS) in a minority of metastatic melanoma (MM) patients. We investigated the role of soluble CTLA-4 (sCTLA-4) as a possible biomarker for identifying this subset of patients. sCTLA-4 levels were analyzed at baseline in sera from 113 IPI-treated MM patients by ELISA, and the median value (200 pg/ml) was used to create two equally sized subgroups. Associations of sCTLA-4 with best overall response (BOR) to IPI and immune-related adverse events (irAEs) were evaluated through logistic regression. Kaplan-Meier and Cox regression methods were used to analyze OS. A remarkable association between sCTLA-4 levels and BOR was found. Specifically, the proportion of patients with sCTLA-4 > 200 pg/ml in irSD or irPD (immune-related stable or progressive disease) was, respectively, 80% (OR = 0.23; 95%CL = 0.03-1.88) and 89% (OR = 0.11; 95%CL = 0.02-0.71) and was lower than that observed among patients in irCR/irPR (immune-related complete/partial response). sCTLA-4 levels increased during IPI treatment, since the proportion of patients showing sCTLA > 200 pg/ml after 3 cycles was 4 times higher (OR = 4.41, 95%CL = 1.02-19.1) than that after 1 cycle. Moreover, a significantly lower death rate was estimated for patients with sCTLA-4 > 200 pg/ml (HR = 0.61, 95%CL = 0.39-0.98). Higher baseline sCTLA-4 levels were also associated with the onset of any irAE (p value = 0.029), in particular irAEs of the digestive tract (p value = 0.041). In conclusion, our results suggest that high sCTLA-4 serum levels might predict favorable clinical outcome and higher risk of irAEs in IPI-treated MM patients.
细胞毒性 T 淋巴细胞相关蛋白 4（CTLA-4）阻断剂伊匹单抗（IPI）可增强少数转移性黑色素瘤（MM）患者的免疫反应并提高总生存期（OS）。我们研究了可溶性 CTLA-4（sCTLA-4）作为识别这类患者的潜在生物标志物的作用。采用 ELISA 法分析了 113 例接受 IPI 治疗的 MM 患者的基线血清 sCTLA-4 水平，采用中位数（200pg/ml）将患者分为两组，每组各 56 例。通过逻辑回归评估 sCTLA-4 与 IPI 最佳总体反应（BOR）和免疫相关不良事件（irAE）之间的相关性。Kaplan-Meier 和 Cox 回归方法用于分析 OS。结果发现 sCTLA-4 水平与 BOR 有显著相关性。具体而言，sCTLA-4 水平>200pg/ml 的 irSD 或 irPD（免疫相关稳定或进展性疾病）患者比例分别为 80%（OR=0.23；95%CI=0.03-1.88）和 89%（OR=0.11；95%CI=0.02-0.71），明显低于 irCR/irPR（免疫相关完全/部分反应）患者。sCTLA-4 水平在 IPI 治疗期间升高，因为在 3 个周期后 sCTLA>200pg/ml 的患者比例是 1 个周期后的 4 倍（OR=4.41，95%CI=1.02-19.1）。此外，sCTLA-4>200pg/ml 的患者的死亡率显著降低（HR=0.61，95%CI=0.39-0.98）。较高的基线 sCTLA-4 水平还与任何 irAE 的发生相关（p 值=0.029），尤其是消化道 irAE（p 值=0.041）。总之，我们的结果表明，高血清 sCTLA-4 水平可能预测接受 IPI 治疗的 MM 患者的临床结局良好，并增加发生 irAE 的风险。
