Morse Michael A, Crosby Erika J, Halperin Daniel M, Uronis Hope E, Hsu S David, Hurwitz Herbert I, Rushing Christel, Bolch Emily K, Warren Dana A, Moyer Ashley N, Lowe Melissa E, Niedzwiecki Donna
Division of Medical Oncology, Duke University Department of Medicine, Durham, North Carolina, USA.
Department of Surgery, Duke University Medical Center, Durham, North Carolina, USA.
J Neuroendocrinol. 2025 Apr;37(4):e13496. doi: 10.1111/jne.13496. Epub 2025 Feb 11.
While performing a study of immune checkpoint blockade with the anti-PD-1 antibody pembrolizumab combined with the somatostatin analogue (SSA) lanreotide in patients with low- and intermediate-grade gastroenteropancreatic neuroendocrine tumors (GEP-NETs), we studied whether there were any immune correlates of response to the anti-PD-1 therapy that could guide future attempts to integrate immunotherapy into the treatment of NETs. Patients with grade 1 and 2 GEP-NETs who had progressed on a prior SSA received lanreotide 90 mg subcutaneously and pembrolizumab 200 mg intravenously every 3 weeks until progression or intolerable toxicity. Objective response rate (ORR) at any time in the study, clinical benefit rate (CBR, defined as stable disease or better), progression-free survival (PFS), and overall survival (OS) were measured. Changes in T cell subsets in peripheral blood before and during therapy were analyzed by multiparameter mass cytometry (CyTOF). Archived tissue samples were analyzed for PD-L1 expression and TIL infiltration. Twenty-two (22) patients (GI/pancreatic 14/8, median Ki67 7% [IQR 4, 10%], median 1.5 prior systemic therapies [range 1-4]) were enrolled. Among the GI-NETs, there was one partial response, the CBR was 50%, the median PFS was 8.5 months, and the median OS was 32.7 months. No responses were seen in pancreatic NETs, which had 0% CBR, a PFS of 2.7 months, and an OS of 23.9 months. Of the 16 analyzable tumors, 6 had detectable PD-L1 expression and 15 had detectable TILs. Neither TILs nor PD-L1 expression correlated with ORR or CBR. However, clinical benefit (SD or better) was associated with peripheral blood on-treatment effector memory T cell activation and progressive disease was associated with baseline peripheral blood regulatory T cell (Treg) activation. We conclude that immune checkpoint blockade had low activity in unselected patients with grade 1 and 2 GEP-NETs. Further study of strategies to reduce Treg activation or enhance effector memory activation during immunotherapy is warranted.
在一项针对低级别和中级胃肠胰神经内分泌肿瘤（GEP-NETs）患者进行的抗程序性死亡蛋白1（PD-1）抗体帕博利珠单抗联合生长抑素类似物（SSA）兰瑞肽的免疫检查点阻断研究中，我们研究了抗PD-1治疗反应是否存在免疫相关因素，这些因素可指导未来将免疫疗法纳入NETs治疗的尝试。先前接受SSA治疗后病情进展的1级和2级GEP-NETs患者，每3周皮下注射90mg兰瑞肽和静脉注射200mg帕博利珠单抗，直至病情进展或出现无法耐受的毒性反应。测量研究中任何时间的客观缓解率（ORR）、临床获益率（CBR，定义为病情稳定或更好）、无进展生存期（PFS）和总生存期（OS）。通过多参数质谱流式细胞术（CyTOF）分析治疗前和治疗期间外周血T细胞亚群的变化。对存档的组织样本进行PD-L1表达和肿瘤浸润淋巴细胞（TIL）浸润分析。纳入了22例患者（胃肠道/胰腺14/8例，Ki67中位数为7%[四分位间距4，10%]，先前全身治疗中位数为1.5次[范围1-4次]）。在胃肠道NETs中，有1例部分缓解，CBR为50%，PFS中位数为8.5个月，OS中位数为32.7个月。胰腺NETs未见缓解，CBR为0%，PFS为2.7个月，OS为23.9个月。在16例可分析的肿瘤中，6例检测到PD-L1表达，15例检测到TILs。TILs和PD-L1表达均与ORR或CBR无关。然而，临床获益（病情稳定或更好）与治疗期间外周血效应记忆T细胞激活相关，疾病进展与基线外周血调节性T细胞（Treg）激活相关。我们得出结论，免疫检查点阻断在未经选择的1级和2级GEP-NETs患者中活性较低。有必要进一步研究在免疫治疗期间降低Treg激活或增强效应记忆激活的策略。
