肿瘤细胞治疗研究
英文原题：First-in-human phase I study of the OX40 agonist GSK3174998 with or without pembrolizumab in patients with selected advanced solid tumors (ENGAGE-1).
GSK3174998 联合 pembrolizumab 在所测试的剂量范围内耐受性良好，并显示出靶点结合。
背景：ENGAGE-1首次人体I期研究评估了人源化IgG1 OX40激动性单克隆抗体GSK3174998单药（第1部分［P1］）或联合pembrolizumab（第2部分［P2］）治疗晚期实体瘤患者的疗效。方法：采用持续再评估法进行剂量递增，每3周静脉给予GSK3174998（0.003–10 mg/kg）联合pembrolizumab（200 mg）。主要目标为安全性和耐受性；次要目标包括药代动力学、免疫原性、药效学及临床活性。结果：共入组138例患者（P1 45例，P2 96例，其中包括3例交叉治疗）。治疗相关不良事件发生率在P1和P2患者中分别为51%和64%，最常见的是疲劳（分别为11%和24%）。未观察到剂量与毒性的关系，也未达到最大耐受剂量。P2剂量限制性毒性包括3级胸腔积液，以及1级心肌炎伴3级肌钙蛋白升高。GSK3174998 0.3 mg/kg显示药代动力学线性特征，且循环T细胞受体占有率超过80%，因此选定该剂量进一步评估。GSK3174998临床活性有限（P1：24周疾病控制率［DCR］9%），未高于pembrolizumab单药预期疗效（P2：总缓解率8%，24周DCR 28%）。配对活检的多重免疫荧光数据提示，肿瘤微环境中自然杀伤（NK）/NKT细胞浸润增加及调节性T细胞（Treg）减少可能促成临床应答：治疗后CD16⁺CD56⁻CD134⁺ NK/NKT细胞和CD3⁺CD4⁺FOXP3⁺CD134⁺ Treg变化幅度最大，而CD3⁺CD8⁺颗粒酶B⁺PD-1⁺CD134⁺细胞毒T细胞变化最小。肿瘤基因表达谱显示，治疗后炎症反应、T细胞增殖及NK细胞功能上调，外周血中部分炎症细胞因子也上调。然而，外周血及肿瘤组织中的药理活性虽证明靶点结合，却与临床疗效无关。应答病例数较少，无法确定稳健的应答预测生物标志物特征。结论：在所测试剂量范围内，GSK3174998联合pembrolizumab耐受性良好并显示靶点结合。其临床活性有限，不支持继续开发该联合方案用于晚期癌症。试验注册号：NCT02528357。
BACKGROUND: The phase I first-in-human study ENGAGE-1 evaluated the humanized IgG1 OX40 agonistic monoclonal antibody GSK3174998 alone (Part 1 (P1)) or in combination with pembrolizumab (Part 2 (P2)) in patients with advanced solid tumors. METHODS: GSK3174998 (0.003-10 mg/kg) pembrolizumab (200 mg) was administered intravenously every 3 weeks using a continuous reassessment method for dose escalation. Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics, immunogenicity, pharmacodynamics, and clinical activity. RESULTS: 138 patients were enrolled (45 (P1) and 96 (P2, including 3 crossovers)). Treatment-related adverse events occurred in 51% (P1) and 64% (P2) of patients, fatigue being the most common (11% and 24%, respectively). No dose-toxicity relationship was observed, and maximum-tolerated dose was not reached. Dose-limiting toxicities (P2) included Grade 3 (G3) pleural effusion and G1 myocarditis with G3 increased troponin. GSK3174998 0.3 mg/kg demonstrated pharmacokinetic linearity and >80% receptor occupancy on circulating T cells; 0.3 mg/kg was selected for further evaluation. Limited clinical activity was observed for GSK3174998 (P1: disease control rate (DCR) 24 weeks 9%) and was not greater than that expected for pembrolizumab alone (P2: overall response rate 8%, DCR 24 weeks 28%). Multiplexed immunofluorescence data from paired biopsies suggested that increased infiltration of natural killer (NK)/natural killer T (NKT) cells and decreased regulatory T cells (Tregs) in the tumor microenvironment may contribute to clinical responses: CD16+CD56-CD134+ NK /NKT cells and CD3+CD4+FOXP3+CD134+ Tregs exhibited the largest magnitude of change on treatment, whereas CD3+CD8+granzyme B+PD-1+CD134+ cytotoxic T cells were the least variable. Tumor gene expression profiling revealed an upregulation of inflammatory responses, T-cell proliferation, and NK cell function on treatment with some inflammatory cytokines upregulated in peripheral blood. However, target engagement, evidenced by pharmacologic activity in peripheral blood and tumor tissue, did not correlate with clinical efficacy. The low number of responses precluded identifying a robust biomarker signature predictive of response. CONCLUSIONS: GSK3174998 pembrolizumab was well tolerated over the dose range tested and demonstrated target engagement. Limited clinical activity does not support further development of GSK3174998 pembrolizumab in advanced cancers. TRIAL REGISTRATION NUMBER: NCT02528357.
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