The aim of this study was to assess the potential value of circulating active and inactive IL-18 levels in distinguishing pseudo and true tumor progression among NSCLC patients receiving immune checkpoint inhibitor treatments (ICIs). Methods: This ancillary study includes 195 patients with metastatic non-small-cell lung cancer (NSCLC) treated with ICI in monotherapy, either pembrolizumab or nivolumab. Plasmatic levels of IL-18-related compounds, comprising the inhibitor IL-18 binding protein (IL-18BP), the inactive IL-18 (corresponding to IL-18/IL-18BP complex), and the active free IL-18, were assayed by ELISA. Objective tumoral response was analyzed by18FDG PET-CT at baseline, 7 weeks, and 3 months post treatment induction, using PERCIST criteria. Results: Plasmatic IL-18BP and total IL-18 levels are increased at baseline in NSCLC patients compared with healthy controls, whereas IL-18/IL-18BP complexes are decreased, and free IL-18 levels remain unchanged. Neither of the IL-18-related compounds allowed to discriminate ICI responding to nonresponding patients. However, inactive IL-18 levels allowed to discriminate patients with a first tumor progression, assessed after 7 weeks of treatment, with worse overall survival. In addition, we showed that neutrophil concentration is also a predictive indicator of patients’ outcomes with OS (HR = 2.6,p= 0.0001) and PFS (HR = 2.2,p= 0.001). Conclusions: Plasmatic levels of inactive IL-18, combined with circulating neutrophil concentrations, can effectively distinguish ICI nonresponding patients with better overall survival (OS), potentially guiding rapid decisions for therapeutic intensification.
本研究旨在评估循环中活性与非活性IL-18水平在区分接受免疫检查点抑制剂（ICIs）治疗的非小细胞肺癌（NSCLC）患者假性与真性肿瘤进展中的潜在价值。方法：本辅助研究纳入195例接受帕博利珠单抗或纳武利尤单抗单药治疗的转移性非小细胞肺癌患者。通过ELISA法检测血浆中IL-18相关化合物水平，包括抑制剂IL-18结合蛋白（IL-18BP）、非活性IL-18（对应IL-18/IL-18BP复合物）及活性游离IL-18。采用PERCIST标准，通过¹⁸FDG PET-CT在基线期、治疗诱导后7周及3个月评估客观肿瘤反应。结果：与健康对照组相比，NSCLC患者基线期血浆IL-18BP和总IL-18水平升高，IL-18/IL-18BP复合物水平降低，游离IL-18水平无显著变化。IL-18相关化合物均无法区分ICI治疗有效与无效患者。然而，非活性IL-18水平可鉴别治疗7周后首次出现肿瘤进展且总生存期较差的患者。此外，研究发现中性粒细胞浓度也是患者总生存期（HR=2.6，p=0.0001）和无进展生存期（HR=2.2，p=0.001）的预测指标。结论：血浆非活性IL-18水平联合循环中性粒细胞浓度可有效鉴别ICI治疗无效但总生存期较好的患者，可能为快速决策强化治疗方案提供指导。
肿瘤(癌症)患者之家