Katsuya Yuki, Kitano Shigehisa, Yamashita Makiko, Ouchi Mayu, Yagishita Shigehiro, Hamada Akinobu, Nakamura Hiromi, Hosoda Fumie, Shibata Tatsuhiro, Motoi Noriko, Nakayama Takayuki, Seto Takashi, Umemura Shigeki, Hosomi Yukio, Satouchi Miyako, Nishio Makoto, Kozuki Toshiyuki, Hida Toyoaki, Ohe Yuichiro, Horinouchi Hidehito
Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.
Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.
Front Oncol. 2023 Jan 9;12:966527. doi: 10.3389/fonc.2022.966527. eCollection 2022.
In a phase II trial of nivolumab in advanced thymic carcinoma (UMIN000022007), long SD (SD for more than 24 weeks) was seen in three patients and irAE (Gr2 or higher) was seen in four patients among 15 patients. Here, we report preplanned comprehensive biomarker analyses. We obtained tumor samples for immunohistochemistry, peripheral blood mononuclear cells (PBMCs), plasma and serum for pharmacokinetic analysis of nivolumab and cytokine evaluations, and whole blood for immuno pharmacogenomic (PGx) analysis. PD-L1 expression on tumor cells were not associated with therapeutic efficacy, but FOXP3 expression in tumor area and stroma, CD204 expression in stroma, and MHC class I in tumor area were all low among long SD patients. PBMC of long SD patients presented with larger number of naïve/memory cells prior to treatment, suggesting priming after nivolumab administration. Immuno-PGx analysis showed non-synonymous SNVs in and had some correlation with PFS. Concentration of nivolumab in blood during the treatment was not related to PFS, with their overall trend towards decreased nivolumab concentration in patients with irAEs. Low immunogenicity of thymic carcinoma demonstrated in our study may require the activation of immune systems a combination of immune checkpoint blockades.
在一项纳武利尤单抗治疗晚期胸腺癌的II期试验（UMIN000022007）中，15例患者中有3例出现了长期疾病稳定（疾病稳定超过24周），4例出现了免疫相关不良反应（2级或更高等级）。在此，我们报告预先计划的综合生物标志物分析。我们获取了用于免疫组织化学的肿瘤样本、用于纳武利尤单抗药代动力学分析和细胞因子评估的外周血单个核细胞（PBMC）、血浆和血清，以及用于免疫药物基因组学（PGx）分析的全血。肿瘤细胞上的PD-L1表达与治疗疗效无关，但长期疾病稳定患者中肿瘤区域和基质中的FOXP3表达、基质中的CD204表达以及肿瘤区域中的MHC I类均较低。长期疾病稳定患者的PBMC在治疗前呈现出更多的幼稚/记忆细胞，提示纳武利尤单抗给药后出现了预激发。免疫PGx分析显示，[具体基因]中的非同义单核苷酸变异与无进展生存期有一定相关性。治疗期间血液中纳武利尤单抗的浓度与无进展生存期无关，免疫相关不良反应患者中纳武利尤单抗浓度总体呈下降趋势。我们的研究表明胸腺癌的免疫原性较低，可能需要激活免疫系统以及联合免疫检查点阻断治疗。
