一项全国多中心前瞻性研究，旨在通过对头颈部癌患者治疗前血浆外泌体mRNA进行全面分析来鉴定预测纳武单抗治疗反应的生物标志物（BIONEXT研究）。
Nationwide multi-centric prospective study for the identification of biomarkers to predict the treatment responses of nivolumab through comprehensive analyses of pretreatment plasma exosome mRNAs from head and neck cancer patients (BIONEXT study).
作者信息
Sato Kuniaki, Toh Satoshi, Murakami Taku, Nakano Takafumi, Hongo Takahiro, Matsuo Mioko, Hashimoto Kazuki, Sugasawa Masashi, Yamazaki Keisuke, Ueki Yushi, Nakashima Torahiko, Uryu Hideoki, Ono Takeharu, Umeno Hirohito, Ueda Tsutomu, Kano Satoshi, Tsukahara Kiyoaki, Watanabe Akihito, Ota Ichiro, Monden Nobuya, Iwae Shigemichi, Maruo Takashi, Asada Yukinori, Hanai Nobuhiro, Sano Daisuke, Ozawa Hiroyuki, Asakage Takahiro, Fukusumi Takahito, Masuda Muneyuki
机构信息
Department of Head and Neck Surgery, National Hospital Organization Kyushu Cancer Center, Fukuoka, Fukuoka, Japan.
Showa Denko Materials America, R&D Center, Irvine, CA, United States.
出版信息
Front Immunol. 2025 Jan 10;15:1464419. doi: 10.3389/fimmu.2024.1464419. eCollection 2024.
BACKGROUND
Nivolumab paved a new way in the treatment of patients with recurrent or metastatic (RM) head and neck squamous cell carcinoma (RM-HNSCC). However, the limited rates of long-term survivors (< 20%) demand a robust prognostic biomarker. This nationwide multi-centric prospective study aimed to identify a plasma exosome (PEX) mRNA signature, which serves as a companion diagnostic of nivolumab and provides a biological clue to develop effective therapies for a majority of non-survivors.
METHODS
Pre-treatment plasmas ( = 104) of RM-HNSCC patients were subjected to comprehensive PEX mRNA analyses for prognostic marker discovery and validation. In parallel, paired treatment-naïve tumor and plasma samples ( = 20) were assayed to elucidate biological implications of the PEX mRNA signature.
RESULTS
Assays for pre-treatment blood samples ( = 104) demonstrated that a combination of 6 candidate PEX mRNAs plus neutrophil-to-lymphocyte ratio precisely distinguished non-survivors from >2-year survivors (2-year OS; 0% vs 57.7%; = 0.000124) with a high hazard ratio of 2.878 (95% CI 1.639-5.055; = 0.0002348). Parallel biological assays demonstrated that in the paired treatment-naïve HNSCC tumor and plasma samples ( = 20), PEX mRNA (a non-survivor-predicting marker) was positively corelated with overexpression of HLA-E protein ( = 0.0191) and the dense population of tumor-infiltrating NK cells ( = 0.024) in the corresponding tumor, suggesting that the HLA-E-NKG2A immune checkpoint may inhibit the antitumor effect of PD-1blockade.
CONCLUSION
The PEX mRNA signature could be useful as a companion diagnostic of nivolumab. The combination of an anti-NKG2A antibody (i.e., monalizumab) and nivolumab may serve as a treatment option for non-survivors predicted by a RT-qPCR-based pre-treatment measurement of PEX mRNAs.
背景
纳武单抗为复发或转移性（RM）头颈部鳞状细胞癌（RM-HNSCC）患者的治疗开辟了一条新途径。然而，长期生存率有限（<20%），需要一种可靠的预后生物标志物。这项全国性多中心前瞻性研究旨在确定一种血浆外泌体（PEX）mRNA特征，作为纳武单抗的伴随诊断标志物，并为大多数非幸存者开发有效治疗方法提供生物学线索。
方法
对RM-HNSCC患者的预处理血浆（n = 104）进行全面的PEX mRNA分析，以发现和验证预后标志物。同时，对配对的未经治疗的肿瘤和血浆样本（n = 20）进行检测，以阐明PEX mRNA特征的生物学意义。
结果
对预处理血液样本（n = 104）的检测表明，6种候选PEX mRNA与中性粒细胞与淋巴细胞比值的组合能够准确区分非幸存者和生存期超过2年的幸存者（2年总生存期；0%对57.7%；P = 0.000124），高风险比为2.878（95%可信区间1.639 - 5.055；P = 0.0002348）。平行生物学检测表明，在配对的未经治疗的HNSCC肿瘤和血浆样本（n = 20）中，PEX mRNA（一种非幸存者预测标志物）与相应肿瘤中HLA-E蛋白的过表达（P = 0.0191）和肿瘤浸润性NK细胞的高密度群体（P = 0.024）呈正相关，提示HLA-E-NKG2A免疫检查点可能抑制PD-1阻断的抗肿瘤作用。
结论
PEX mRNA特征可作为纳武单抗的有用伴随诊断标志物。抗NKG2A抗体（即莫那利珠单抗）与纳武单抗联合使用，可能是通过基于RT-qPCR的预处理PEX mRNA检测预测的非幸存者的一种治疗选择。
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