Introduction Immunotherapy has resulted in pathologic responses in hepatocellular carcinoma (HCC), but the benefits and molecular mechanisms of neoadjuvant immune checkpoint blockade are largely unknown. Methods In this study, we evaluated the efficacy and safety of preoperative nivolumab (anti-PD-1) in patients with intermediate and locally advanced HCC and determined the molecular markers for predicting treatment response. Results Between July 2020 and November 2021, 20 treatment-naive HCC patients with intermediate and locally advanced tumors received preoperative nivolumab at 3 mg/kg for 3 cycles prior to surgical resection. Nineteen patients underwent surgical resection on trial. Seven (36.8%) of the 19 patients had major pathologic tumor necrosis (≥60%) in the post-nivolumab resection specimens, with 3 having almost complete (>90%) tumor necrosis. The tumor necrosis was hemorrhagic and often accompanied by increased or dense immune cell infiltrate at the border of the tumors. None of the patients developed major adverse reactions contradicting hepatectomy. RNA-sequencing analysis on both pre-nivolumab tumor biopsies and post-nivolumab resected specimens showed that, in cases with major pathologic necrosis, the proportion of CD8 T cells in the HCC tissues predominantly increased after treatment. Moreover, to investigate noninvasive biomarker for nivolumab response, we evaluated the copy number variation (CNV) using target-panel sequencing on plasma cell-free DNA of the patients and derived a CNV-based anti-PD-1 score. The score correlated with the extent of tumor necrosis and was validated in a Korean patient cohort with anti-PD-1 treatment. Conclusion Neoadjuvant nivolumab demonstrated promising clinical activity in intermediate and locally advanced HCC patients. We also identified useful noninvasive biomarker predicting responsiveness.

中文翻译：

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纳武利尤单抗新辅助治疗中晚期和局部晚期肝细胞癌的多模式综合基因组学和病理学分析。


引言免疫疗法已导致肝细胞癌 （HCC） 的病理反应，但新辅助免疫检查点阻断的益处和分子机制在很大程度上尚不清楚。方法 在本研究中，我们评估了术前纳武利尤单抗 （anti-PD-1） 在中晚期和局部晚期 HCC 患者中的疗效和安全性，并确定了预测治疗反应的分子标志物。结果 2020 年 7 月至 2021 年 11 月期间，20 例初治的中晚期和局部晚期肿瘤 HCC 患者在手术切除前接受了 3 mg/kg 的纳武利尤单抗治疗，持续 3 个周期。19 例患者在试验中接受了手术切除。19 例患者中有 7 例 （36.8%） 在纳武利尤单抗切除术后标本中有 ≥60%） 严重病理性肿瘤坏死，其中 3 例几乎完全 （>90%） 肿瘤坏死。肿瘤坏死为出血性，常伴有肿瘤边界免疫细胞浸润增加或致密。所有患者均未出现与肝切除术相矛盾的重大不良反应。对 nivolumab 前肿瘤活检和 nivolumab 切除后标本的 RNA 测序分析显示，在严重病理坏死的病例中，治疗后 HCC 组织中 CD8 T 细胞的比例主要增加。此外，为了研究 nivolumab 反应的无创生物标志物，我们使用患者血浆游离 DNA 的靶标面板测序评估了拷贝数变异 （CNV），并得出了基于 CNV 的抗 PD-1 评分。该评分与肿瘤坏死的程度相关，并在接受抗 PD-1 治疗的韩国患者队列中得到验证。结论 新辅助纳武利尤单抗在中度和局部晚期 HCC 患者中显示出有前景的临床活性。 我们还确定了预测反应性的有用无创生物标志物。