Personeni Nicola, Pressiani Tiziana, D'Alessio Antonio, Prete Maria Giuseppina, Bozzarelli Silvia, Terracciano Luigi, Dal Buono Arianna, Capogreco Antonio, Aghemo Alessio, Lleo Ana, Lutman Romano Fabio, Roncalli Massimo, Giordano Laura, Santoro Armando, Di Tommaso Luca, Rimassa Lorenza
Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy.
Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy.
Cancers (Basel). 2021 Nov 12;13(22):5665. doi: 10.3390/cancers13225665.
Risk factors for hepatic immune-related adverse events (HIRAEs) in patients with advanced/unresectable hepatocellular carcinoma (HCC) treated with immune checkpoint inhibitors (ICIs) are unclear. We investigated: (i) clinical and morpho-pathological predictors of HIRAEs in 27 pretreatment tumor specimens, including surrogate biomarkers of the HCC immune class (based on intratumoral tertiary lymphoid structures, and glutamine synthase, CD3, and CD79 expression); and (ii) the relationship between HIRAE onset and subsequent treatment outcomes. Fifty-eight patients were included-20 (34%) received ICIs alone, and 38 (66%) received ICIs plus targeted agents as first- or further-line treatment. After a median time of 0.9 months (range, 0.4-2.7), nine patients (15.5%) developed grade ≥ 3 hepatitis, which was significantly associated with higher baseline ALT levels ( = 0.037), and an infectious HCC etiology ( = 0.023). ICIs were safely resumed in six out of nine patients. Time to treatment failure (TTF) was not significantly different in patients developing grade ≥ 3 hepatitis vs. lower grades (3.25 vs. 3.91 months, respectively; = 0.81). Biomarker surrogates for the HCC immune class were not detected in patients developing grade ≥ 3 hepatitis. Grade ≥ 3 hepatitis has a benign course that does not preclude safe ICI reintroduction, without any detrimental effect on TTF.
接受免疫检查点抑制剂（ICI）治疗的晚期/不可切除肝细胞癌（HCC）患者发生肝脏免疫相关不良事件（HIRAE）的风险因素尚不清楚。我们进行了以下研究：（i）在27份治疗前肿瘤标本中研究HIRAE的临床和形态病理学预测因素，包括HCC免疫类别（基于肿瘤内三级淋巴结构、谷氨酰胺合成酶、CD3和CD79表达）的替代生物标志物；（ii）HIRAE发生与后续治疗结果之间的关系。纳入了58例患者，其中20例（34%）仅接受ICI治疗，38例（66%）接受ICI联合靶向药物作为一线或后续治疗。中位时间为0.9个月（范围0.4 - 2.7个月）后，9例患者（15.5%）发生≥3级肝炎，这与更高的基线ALT水平（P = 0.037）和感染性HCC病因（P = 0.023）显著相关。9例患者中有6例安全恢复使用ICI。发生≥3级肝炎的患者与较低级别肝炎患者的治疗失败时间（TTF）无显著差异（分别为3.25个月和3.91个月；P = 0.81）。发生≥3级肝炎的患者未检测到HCC免疫类别的生物标志物替代物。≥3级肝炎病程良性，不排除安全重新引入ICI，对TTF无任何不利影响。
