Predictive biomarkers for the efficacy of peptide vaccine treatment: based on the results of a phase II study on advanced pancreatic cancer.
Predictive biomarkers for the efficacy of peptide vaccine treatment: based on the results of a phase II study on advanced pancreatic cancer.
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肽疫苗治疗功效的预测生物标志物：基于晚期胰腺癌 II 期研究的结果。
DOI：
10.1186/s13046-017-0509-1
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发表时间：
2017-02-28
期刊：
影响因子：
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通讯作者：
Nagano H
中科院分区：
文献类型：
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作者：
Shindo Y;Hazama S;Suzuki N;Iguchi H;Uesugi K;Tanaka H;Aruga A;Hatori T;Ishizaki H;Umeda Y;Fujiwara T;Ikemoto T;Shimada M;Yoshimatsu K;Takenouchi H;Matsui H;Kanekiyo S;Iida M;Koki Y;Arima H;Furukawa H;Ueno T;Yoshino S;Fujita T;Kawakami Y;Nakamura Y;Oka M;Nagano H
本研究的目的是探索新的生物标志物，可以预测治疗前或疫苗接种期间患者的临床结果。这些将有助于选择合适的患者，这些患者预计将通过疫苗接种表现出更好的治疗效果，并促进癌症疫苗治疗的开发。从一个单臂，非随机，人类白细胞抗原（HLA）-A状态盲II期试验的疫苗治疗使用三个HLA-A*2402限制性肽晚期胰腺癌（PC），我们获得了外周血样本，从36例患者的HLA-A*2402匹配组和27例患者的HLA-A*2402不匹配组。多变量分析（HR = 2.546; 95%CI = 1.138 - 5.765; p = 0.0231）和对数秩检验（p = 0.0036）显示，CD 4 + T细胞上程序性死亡-1（PD-1）的高表达水平是HLA-A*2402匹配组总生存期的阴性预测生物标志物。此外，CD 4 + T细胞上PD-1的高表达水平是诱导细胞毒性T淋巴细胞的阴性预测因子（p = 0.0007）。治疗后，我们发现，在HLA-A*2402匹配组中，CD 4+和CD 8 + T细胞上PD-1和T细胞免疫球蛋白粘蛋白-3（Tim-3）表达的上调与不良临床结局显著相关（分别为p = 0.0330、0.0282、0.0046和0.0068）。相反，在HLA-A*2402不匹配组中，这些因素没有显著差异。我们的研究结果表明，PD-1和Tim-3在CD 4+和CD 8 + T细胞上的表达上调可能会限制晚期PC患者的T细胞应答;因此，联合免疫治疗与PD-1和Tim-3的阻断以恢复T细胞应答可能是晚期PC患者的潜在治疗方法。临床试验注册：UMIN 000008082。本文的在线版本（doi：10.1186/s13046-017-0509-1）包含补充材料，可供授权用户使用。
The purpose of the present study was to explore novel biomarkers that can predict the clinical outcome of patients before treatment or during vaccination. These would be useful for the selection of appropriate patients who would be expected to exhibit better treatment outcomes from vaccination, and for facilitating the development of cancer vaccine treatments. From a single-arm, non-randomized, human leukocyte antigen (HLA)-A-status-blind phase II trial of a vaccine treatment using three HLA-A*2402-restricted peptides for advanced pancreatic cancer (PC), we obtained peripheral blood samples from 36 patients of an HLA-A*2402-matched group and 27 patients of an HLA-A*2402-unmatched group. Multivariate analysis (HR = 2.546; 95% CI = 1.138 to 5.765; p = 0.0231) and log-rank test (p = 0.0036) showed that a high expression level of programmed death-1 (PD-1) on CD4+ T cells was a negative predictive biomarker of overall survival in the HLA-A*2402-matched group . Moreover, a high expression level of PD-1 on CD4+ T cells was a negative predictor for the induction of cytotoxic T lymphocytes (p = 0.0007). After treatment, we found that the upregulation of PD-1 and T cell immunoglobulin mucin-3 (Tim-3) expression on CD4+ and CD8+ T cells was significantly associated with a poor clinical outcome in the HLA-A*2402-matched group (p = 0.0330, 0.0282, 0.0046, and 0.0068, respectively). In contrast, there was no significant difference for these factors in the HLA-A*2402-unmatched group. Our results indicate that the upregulation of PD-1 and Tim-3 expression on CD4+ and CD8+ T cells may restrict T cell responses in advanced PC patients; therefore, combination immunotherapy with blockade of PD-1 and Tim-3 to restore T cell responses may be a potential therapeutic approach for advanced PC patients. Clinical-Trail-Registration: UMIN000008082. The online version of this article (doi:10.1186/s13046-017-0509-1) contains supplementary material, which is available to authorized users.