第一人类试验ENGAGE-1评估了人源化IgG1 OX40激动单克隆抗体GSK3174998在晚期实体瘤患者中单独使用（第一部分P1）或与pembrolizumab联合使用（第二部分P2）。使用连续评估方法进行剂量逐步上升，每3周静脉注射GSK3174998（0.003-10mg/kg）± pembrolizumab（200mg）。主要目标是安全性和耐受性；次要目标包括药代动力学、免疫原性、药效学和临床活性。共招募了138名患者（其中P1 45名，P2 96名，包括3名交叉）。治疗相关的不良事件发生率为51％（P1）和64％（P2），疲劳是最常见的不良事件（分别为11％和24％）。未观察到剂量毒性关系，最大耐受剂量未达到。剂量限制性毒性（P2）包括3级胸腔积液和1级心肌炎与3级肌钙蛋白增高。GSK3174998 ≥0.3mg/kg展示了药代动力学线性和> 80％的循环T细胞受体占位率；选择0.3mg/kg进行进一步评估。GSK3174998的临床活性有限（P1：疾病控制率（DCR） ≥24周为9％），并且不比与pembrolizumab单独使用（P2：总体响应率8％，DCR ≥24周为28％）更大。来自搭配活检的多重免疫荧光数据表明，肿瘤微环境中的天然杀伤细胞（NK）/天然杀伤T细胞（NKT）细胞的浸润增加和调节性T细胞（Tregs）的减少可能有助于临床治疗反应：CD16 + CD56- CD134 + NK / NKT细胞和CD3 + CD4 + FOXP3 + CD134 + Tregs在治疗中表现出最大的变化幅度，而CD3 + CD8 + granzyme B + PD-1 + CD134 + 细胞毒性T细胞变化最小。肿瘤基因表达谱揭示了在使用一些炎性细胞因子上调时出现了炎性反应、T细胞增殖和NK细胞功能上调的情况。然而，证明在外周血液和肿瘤组织中具有药理活性的标靶并不相关临床疗效。低反应率排除了鲜明的预测反应的强有力生物标记签名。GSK3174998 ± pembrolizumab经过测试的剂量范围内耐受良好，已显示出目标靶向。有限的临床活性不支持在晚期癌症中进一步开发GSK3174998 ± pembrolizumab.NCT02528357.©作者（或他们的雇主）2023年。根据CC BY-NC允许重用，不得商业重用。由BMJ发布。

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.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.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.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.NCT02528357.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.