Advanced pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Immunotherapy alone offers limited efficacy, but it is still unknown whether its combination with chemotherapy could offer synergistic anti-tumor effects. This phase Ib/II study evaluated the safety and efficacy of combining toripalimab with the gemcitabine plus nab-paclitaxel (GnP) regimen as first-line treatment for locally advanced or metastatic PDAC and explored predictive biomarkers (ChiCTR2000032293). The primary endpoints were safety and overall survival (OS). The secondary outcomes were objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Immune-related biomarkers including programmed death-ligand 1 (PD-L1) expression, genetic status, cytokine levels, and spatial features of the tumor immune microenviroment (TIME) were investigated. Neither serious treatment-related adverse events nor grade 4 immune-related adverse events were reported. Among the 72 patients, the median OS was 8.9 months, 12-month OS rate was 31.9%, with median PFS of 5.6 months, ORR of 33.3%, and DCR of 90.3%. Higher PD-L1 expression, without liver metastases were associated with higher ORR, however these factors could not effectively distinguish responders and non-responders. Importantly, dendritic cells - T helper cells - cytotoxic T lymphocytes (DC-Th-CTL) enriched immune niche and their spatial interactions were dominant predictors of response based on TIME analysis using a cyclic multiplex tissue staining assay, with an area under the curve value of 0.8. Overall, GnP plus toripalimab exhibited good safety and differentiated efficacy in selected population, and the spatial interactions of DC-Th-CTL represent promising predictors to efficacy of immunochemotherapy in locally advanced or metastatic PDAC.

晚期胰腺导管腺癌 （PDAC） 的预后不佳。单独的免疫疗法疗效有限，但其与化疗的联合治疗是否能提供协同抗肿瘤作用仍是未知数。这项 Ib/II 期研究评估了特瑞普利单抗与吉西他滨联合白蛋白结合型紫杉醇 （GnP） 方案作为局部晚期或转移性 PDAC 一线治疗的安全性和有效性，并探讨了预测生物标志物 （ChiCTR2000032293）。主要终点是安全性和总生存期 （OS）。次要结局是客观缓解率 （ORR） 、疾病控制率 （DCR） 和无进展生存期 （PFS）。研究免疫相关生物标志物，包括程序性死亡配体 1 （PD-L1） 表达、遗传状态、细胞因子水平和肿瘤免疫微环境 （TIME） 的空间特征。未报告严重的治疗相关不良事件和 4 级免疫相关不良事件。在 72 例患者中，中位 OS 为 8.9 个月，12 个月 OS 率为 31.9%，中位 PFS 为 5.6 个月，ORR 为 33.3%，DCR 为 90.3%。较高的 PD-L1 表达，无肝转移与较高的 ORR 相关，但这些因素不能有效区分反应者和无反应者。重要的是，树突状细胞 - T 辅助细胞 - 细胞毒性 T 淋巴细胞 （DC-Th-CTL） 富集的免疫生态位及其空间相互作用是基于使用循环多重组织染色测定的 TIME 分析的反应的主要预测因子，曲线下面积值为 0.8。 总体而言，GnP 联合特瑞普利单抗在选定人群中表现出良好的安全性和差异化疗效，DC-Th-CTL 的空间相互作用代表了免疫化疗在局部晚期或转移性 PDAC 中疗效的有希望的预测因子。