表达在活化的T细胞和自然杀伤细胞上,4-1BB/CD137是一种共刺激受体,其发出导致细胞因子分泌和增强的效应子功能的一系列事件的信号。用激动剂抗体靶向4-1BB/CD137与肿瘤减少和抗肿瘤免疫有关。C-C趋化因子受体4(CCR4)在各种实体瘤适应症中高表达,并与预后不良有关。这个阶段Ib,晚期实体瘤患者的开放标签研究评估了安全性,功效,药代动力学,和奥托单抗(PF-05082566)的药效学,T细胞共刺激受体4-1BB/CD137的人单克隆抗体(mAb)激动剂,与莫加单抗联合使用,据报道,靶向CCR4的人源化mAb耗尽调节性T细胞(Tregs)的亚群。
将Utomilumab1.2-5mg/kg或每4周100mg统一剂量加莫加单抗1mg/kg(在第1周期中每周一次,然后在周期≥2周期中每两周一次)静脉内给予24名患有实体瘤的成年人。在给药前和给药后收集血液以评估药物药代动力学,免疫原性,和药效学标志物。还分析了一部分患者的基线肿瘤活检是否存在程序性细胞死亡配体1(PD-L1),CD8、FoxP3和4-1BB/CD137。在基线和每8周治疗时进行放射学肿瘤评估。
没有发生剂量限制性毒性,并且根据事件发生时间连续重新评估方法,最大耐受剂量确定为至少2.4mg/kg。未观察到与任一治疗相关的严重不良事件;贫血是与两种治疗相关的唯一3级非严重不良事件。Utomilumab全身暴露似乎随剂量增加。1名PD-L1难治性鳞状细胞肺癌患者获得了部分反应的最佳总体反应,9名患者获得了稳定疾病的最佳总体反应。没有患者达到完全缓解。根据RECIST1.1,客观反应率为4.2%(95%置信区间:0.1-21.1%)。如通过T细胞受体序列分析所评估的,外周血中Tregs的耗尽伴随有T细胞扩增的证据。
奥托单抗/莫加穆利珠单抗的组合是安全和可耐受的,并且可以适合于在表达CCR4的Treg抑制抗癌免疫的环境中进行评估。
ClinicalTrials.gov标识符:NCT02444793。
Expressed on activated T and natural killer cells, 4-1BB/
CD137 is a costimulatory receptor that signals a series of events resulting in cytokine secretion and enhanced effector function. Targeting 4-1BB/
CD137 with agonist antibodies has been associated with tumor reduction and antitumor immunity. C-C chemokine receptor 4 (CCR4) is highly expressed in various solid tumor indications and associated with poor prognosis. This phase Ib, open-label
study in patients with advanced solid tumors assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of utomilumab (PF-05082566), a human monoclonal antibody (mAb) agonist of the T-cell costimulatory receptor 4-1BB/
CD137, in combination with mogamulizumab, a humanized mAb targeting CCR4 reported to deplete subsets of regulatory T cells (Tregs).
Utomilumab 1.2-5 mg/kg or 100 mg flat dose every 4 weeks plus mogamulizumab 1 mg/kg (weekly in Cycle 1 followed by biweekly in Cycles ≥2) was administered intravenously to 24 adults with solid tumors. Blood was collected pre- and post-dose for assessment of drug pharmacokinetics, immunogenicity, and pharmacodynamic markers. Baseline tumor biopsies from a subset of patients were also analyzed for the presence of programmed cell death-ligand 1 (PD-L1), CD8, FoxP3, and 4-1BB/
CD137. Radiologic tumor assessments were conducted at baseline and on treatment every 8 weeks.
No dose-limiting toxicities occurred and the maximum tolerated dose was determined to be at least 2.4 mg/kg per the time-to-event continual reassessment method. No serious adverse events related to either treatment were observed; anemia was the only grade 3 non-serious adverse event related to both treatments. Utomilumab systemic exposure appeared to increase with dose. One patient with PD-L1-refractory squamous lung cancer achieved a best overall response of partial response and 9 patients had a best overall response of stable disease. No patients achieved complete response. Objective response rate was 4.2% (95% confidence interval: 0.1-21.1%) per RECIST 1.1. Depletion of Tregs in peripheral blood was accompanied by evidence of T-cell expansion as assessed by T-cell receptor sequence analysis.
The combination of utomilumab/mogamulizumab was safe and tolerable, and may be suitable for evaluation in settings where CCR4-expressing Tregs are suppressing anticancer immunity.
ClinicalTrials.gov identifier: NCT02444793.