Department of Experimental Therapeutics, National Cancer Center Hospital East, Chiba, Japan.
Clinical Oncology and Outpatient Treatment Center, Aichi Cancer Center Hospital, Nagoya, Japan.
Clin Cancer Res. 2019 Nov 15;25(22):6614-6622. doi: 10.1158/1078-0432.CCR-19-1090. Epub 2019 Aug 27.
Regulatory T cells (Tregs) expressing CC chemokine receptor 4 (CCR4) can suppress antitumor immune responses and are associated with poor prognoses in several cancers. We assessed the safety and efficacy of combined mogamulizumab (anti-CCR4 antibody) and nivolumab [anti-programmed death-1 (PD-1) antibody] in immunotherapy-naïve patients with advanced/metastatic solid tumors.
This study (NCT02476123) comprised dose-escalation (3+3 design) and expansion parts. Patients received nivolumab (3.0 mg/kg) every 2 weeks, with mogamulizumab (0.3 or 1.0 mg/kg in dose escalation, 1.0 mg/kg in expansion) once weekly for 4 weeks, then every 2 weeks, until progression or unacceptable toxicity. Primary objective was safety; secondary objectives were antitumor effects, pharmacokinetics, and immunogenicity. Exploratory biomarker analyses were conducted.
Ninety-six patients were enrolled (July 2015-November 2016): six patients in the dose-escalation part and 90 in the expansion part. No dose-limiting toxicities were observed in the dose-escalation part. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 29% of patients in the expansion part (no grade 5 TRAEs). The most frequent TRAEs were rash (39%), rash maculopapular (20%), diarrhea (13%), stomatitis (12%), and pruritus (11%). There were four (27%) confirmed tumor responses among 15 patients with hepatocellular carcinoma, and one confirmed and two unconfirmed responses among 15 patients with pancreatic adenocarcinoma. During treatment, populations of effector Tregs (CD4CD45RAFoxP3) decreased and CD8 T cells in tumor-infiltrating lymphocytes increased.
Combining an anti-PD-1 antibody, nivolumab, with a Treg-depleting anti-CCR4 antibody, mogamulizumab, provides an acceptable safety profile, antitumor activity, and a potentially effective option in cancer immunotherapy.
表达 C 型趋化因子受体 4（CCR4）的调节性 T 细胞（Tregs）可抑制抗肿瘤免疫反应，并与几种癌症的不良预后相关。我们评估了莫加木单抗（抗 CCR4 抗体）联合纳武单抗（抗程序性死亡-1（PD-1）抗体）在免疫治疗初治的晚期/转移性实体瘤患者中的安全性和有效性。
这项研究（NCT02476123）包括剂量递增（3+3 设计）和扩展部分。患者每 2 周接受纳武单抗（3.0mg/kg），在剂量递增中每 4 周接受莫加木单抗（0.3 或 1.0mg/kg），在扩展中每周接受 1.0mg/kg，然后每 2 周一次，直到疾病进展或不可接受的毒性。主要目的是安全性；次要目的是抗肿瘤作用、药代动力学和免疫原性。进行了探索性生物标志物分析。
共纳入 96 例患者（2015 年 7 月至 2016 年 11 月）：剂量递增部分 6 例，扩展部分 90 例。在剂量递增部分未观察到剂量限制毒性。在扩展部分，39%的患者出现 3/4 级治疗相关不良事件（TRAEs）（无 5 级 TRAEs）。最常见的 TRAEs 是皮疹（39%）、斑丘疹（20%）、腹泻（13%）、口腔炎（12%）和瘙痒（11%）。15 例肝细胞癌患者中有 4 例（27%）确认肿瘤有反应，15 例胰腺腺癌患者中有 1 例确认和 2 例未确认的反应。在治疗期间，效应 Tregs（CD4+CD45RA+FoxP3+）的数量减少，肿瘤浸润淋巴细胞中的 CD8+T 细胞增加。
抗 PD-1 抗体纳武单抗联合 Treg 耗竭性抗 CCR4 抗体莫加木单抗具有可接受的安全性、抗肿瘤活性，并为癌症免疫治疗提供了一种潜在有效的选择。
