ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8⁺ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.

ADAPTeR 是一项针对 15 名未接受过治疗的转移性透明细胞肾细胞癌 (ccRCC) 患者（115 个多区域肿瘤样本）的 nivolumab（抗 PD-1）的前瞻性 II 期研究，旨在了解支持治疗反应的机制。基因组分析显示肿瘤分子特征和反应之间没有相关性，而 ccRCC 特异性人内源性逆转录病毒表达与临床反应间接相关。T 细胞受体 (TCR) 分析显示，在反应者中扩增的 TCR 克隆数量显着增加，表明预先存在免疫。治疗后维持高度相似的 TCR 簇可预测反应，表明可能识别相同抗原的 T 细胞家族的持续抗原参与和存活。在响应者中，纳武单抗结合的 CD8 ⁺T 细胞扩增并表达 GZMK/B。我们的数据表明，纳武利尤单抗驱动先前扩增的 T 细胞克隆的维持和替换，但只有维持与反应相关。我们假设维持和增强预先存在的反应是抗 PD-1 作用模式的关键要素。