Table_1_Increased Circulating Levels of CRP and IL-6 and Decreased Frequencies of T and B Lymphocyte Subsets Are Associated With Immune-Related Adverse Events During Combination Therapy With PD-1 Inhibitors for Liver Cancer.pdf

BackgroundProgrammed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune-related adverse events (irAEs) are inevitable in patients with liver cancer. Although the incidence of severe irAEs is low, but can result in fatal consequences. To date, only a few commonly used clinical biomarkers have been reported.
AimTo assess commonly used clinical biomarkers associated with the occurrence of irAEs to enable better management of irAEs by clinicians.
MethodsWe retrospectively reviewed patients with liver cancer treated with at least one cycle of PD-1 immune checkpoint inhibitors (ICIs) combined with tyrosine kinase inhibitors (TKIs). IrAEs were documented according to the common terminology criteria for adverse events version 5. Clinical and laboratory parameters were also evaluated.
ResultsA total of 67 patients were included, 36 with irAEs and 31 without irAEs. A total of 104 adverse events occurred; 83 of these events were grade 1/2 (G1/G2), 21 were grade 3/4 (G3/G4), and one died of G4 hepatitis. Patients with irAEs had higher levels of C-reactive protein (CRP) and interleukin-6 (IL-6) and lower levels of lymphocyte subsets, except natural killer (NK) cell counts, than those without irAEs (P <0.05). Patients who experienced G3/G4 irAEs had higher levels of CRP and IL-6 and lower levels of CD4+ T lymphocytes and B lymphocytes than those who experienced G1/G2 irAEs (P <0.05). Of note, impairments in liver function and routine blood tests were also observed (P <0.05). The results of univariate and multivariate analyses for any grade of irAEs revealed that the combination of sintilimab and lenvatinib (P= 0.004, odds ratio [OR]: 7.414, 95% confidence interval [95% CI]: 1.925–28.560) and CRP ≥8.2 mg/L (P= 0.024, OR: 3.727, CI: 1.185–11.726) were independent risk factors. Univariate and multivariate analyses of the risk factors of G3/G4 irAEs suggested that the combination of sintilimab and lenvatinib was a potential risk factor (P = 0.049, OR: 8.242, CI: 1.006–67.532).
ConclusionChanges in patient CRP, IL-6, and lymphocyte subsets were associated with irAE onset and may act as potential biomarkers of irAEs. Impairments in liver function and routine blood tests owing to the occurrence of irAEs may become new concerns for clinicians.

背景：肝癌患者接受PD-1/PD-L1抑制剂治疗时，程序性死亡蛋白1/程序性死亡配体1（PD-1/PD-L1）相关免疫不良事件（irAEs）不可避免。尽管重度irAEs的发生率较低，但可导致致命性后果。截至目前，仅有少数常用临床生物标志物被报道。

目的：本研究旨在评估与irAEs发生相关的常用临床生物标志物，以助力临床医师更好地管理免疫相关不良事件。

方法：本研究回顾性分析了接受至少1个周期PD-1免疫检查点抑制剂（ICIs）联合酪氨酸激酶抑制剂（TKIs）治疗的肝癌患者。免疫不良事件依据不良事件通用术语标准第5版（CTCAE v5）进行记录，同时对患者的临床及实验室指标进行评估。

结果：最终纳入67例患者，其中36例发生irAEs，31例未发生irAEs。共计发生104例次不良事件，其中83例为1/2级（G1/G2），21例为3/4级（G3/G4），1例因4级肝炎死亡。与未发生irAEs的患者相比，发生irAEs的患者C反应蛋白（CRP）、白细胞介素6（IL-6）水平更高，而除自然杀伤（NK）细胞外的淋巴细胞亚群水平更低（P<0.05）。与发生G1/G2级irAEs的患者相比，发生G3/G4级irAEs的患者CRP、IL-6水平更高，CD4+T淋巴细胞及B淋巴细胞水平更低（P<0.05）。值得注意的是，研究还观察到肝功能及血常规指标存在异常改变（P<0.05）。针对任意级别irAEs的单因素及多因素分析结果显示，信迪利单抗（sintilimab）联合仑伐替尼（lenvatinib）（P=0.004，比值比[OR]=7.414，95%置信区间[95%CI]：1.925~28.560）以及CRP≥8.2mg/L（P=0.024，OR=3.727，95%CI：1.185~11.726）为独立危险因素。针对G3/G4级irAEs危险因素的单因素及多因素分析结果显示，信迪利单抗联合仑伐替尼为潜在危险因素（P=0.049，OR=8.242，95%CI：1.006~67.532）。

结论：患者CRP、IL-6及淋巴细胞亚群的水平变化与irAEs的发生相关，可作为irAEs的潜在生物标志物。因irAEs导致的肝功能及血常规指标异常，或可成为临床医师新的关注重点。