需要新的联合治疗方案以克服抗PD-1耐药性。Enadenotucirev是一种肿瘤选择性的血液稳定性腺病毒载体，在固体肿瘤的I期研究中展示了可以控制的安全性和增加肿瘤免疫细胞浸润的能力。我们对晚期/转移上皮癌患者进行了一项多中心I期研究，研究了静脉注射Enadenotucirev加nivolumab的治疗效果，这些患者对标准治疗没有反应。该研究的共同主要目标是评估Enadenotucirev加nivolumab的安全性/耐受性以及最大耐受剂量和/或最大可行剂量（MTD / MFD）。其他终点包括响应率、细胞因子反应和抗肿瘤免疫反应。总体上，治疗了51名重度预处理的患者，其中45 / 51（88％）患有结直肠癌（35/35名患者信息可用的微卫星不稳定型/微卫星稳定型），6/51（12％）患有头颈鳞癌。Enadenotucirev加nivolumab的MTD / MFD没有达到，最高剂量水平（1×1012 vp第1天；6×1012 vp第3天和第5天）被证明是可以承受的。总体而言，31/51（61％）患者经历了3-4级治疗新发不良事件（TEAE），最常见的是贫血（12％），输注相关反应（8％），低钠血症（6％）和大肠梗阻（6％）。有7（14％）名患者经历了与Enadenotucirev相关的TEAE，与Enadenotucirev相关的唯一的严重TEAE发生在> 1名患者中即输注相关反应（n = 2）。在47名纳入疗效分析的患者中，中位无进展生存期为1.6个月，客观反应率为2％（1个偏离应答10个月），45％的患者实现了疾病稳定。中位总生存期为16.0个月，12个月时69％的患者仍然活着。两名患者从约第15天开始出现Th1和相关细胞因子（IFNγ，IL-12p70，IL-17A）的持续增加，其中一人出现了部分反应。在14名具有匹配的癌前和癌后活检的患者中，12名患者肿瘤内CD8 + T细胞浸润增加，7名患者CD8 T细胞细胞溶解活性标记增加。静脉注射Enadenotucirev加nivolumab表现出可控的耐受性，鼓舞人心的总生存期并在晚期/转移上皮癌患者中诱导免疫细胞浸润和激活。正在进行一些研究，以探讨进一步重编程肿瘤微环境、表达免疫增强剂基因的Enadenotucirev下一代变体（T-SIGn载体）的疗效。NCT02636036。© 作者（或其雇主）2023年。经CC BY-NC许可重用。无商业再利用。由BMJ出版。

Novel combination therapies to overcome anti-PD-1 resistance are required. Enadenotucirev, a tumor-selective blood stable adenoviral vector, has demonstrated a manageable safety profile and ability to increase tumor immune-cell infiltration in phase I studies in solid tumors.We conducted a phase I multicenter study of intravenous enadenotucirev plus nivolumab in patients with advanced/metastatic epithelial cancer not responding to standard therapy. Co-primary objectives were safety/tolerability and maximum tolerated dose and/or maximum feasible dose (MTD/MFD) of enadenotucirev plus nivolumab. Additional endpoints included response rate, cytokine responses, and anti-tumor immune responses.Overall, 51 heavily pre-treated patients were treated, 45/51 (88%) of whom had colorectal cancer (35/35 patients with information available were microsatellite instability-low/microsatellite stable) and 6/51 (12%) had squamous cell carcinoma of the head and neck. The MTD/MFD of enadenotucirev plus nivolumab was not reached, with the highest dose level tested (1×1012 vp day 1; 6×1012 vp days 3 and 5) shown to be tolerable. Overall, 31/51 (61%) patients experienced a grade 3-4 treatment-emergent adverse event (TEAE), most frequently anemia (12%), infusion-related reaction (8%), hyponatremia (6%), and large intestinal obstruction (6%). Seven (14%) patients experienced serious TEAEs related to enadenotucirev; the only serious TEAE related to enadenotucirev occurring in >1 patient was infusion-related reaction (n=2). Among the 47 patients included in efficacy analyses, median progression-free survival was 1.6 months, objective response rate was 2% (one partial response for 10 months), and 45% of patients achieved stable disease. Median overall survival was 16.0 months; 69% of patients were alive at 12 months. Persistent increases in Th1 and related cytokines (IFNγ, IL-12p70, IL-17A) were seen from ~day 15 in two patients, one of whom had a partial response. Among the 14 patients with matching pre-tumor and post-tumor biopsies, 12 had an increase in intra-tumoral CD8+ T-cell infiltration and 7 had increased markers of CD8 T-cell cytolytic activity.Intravenously dosed enadenotucirev plus nivolumab demonstrated manageable tolerability, an encouraging overall survival and induced immune cell infiltration and activation in patients with advanced/metastatic epithelial cancer. Studies of next-generation variants of enadenotucirev (T-SIGn vectors) designed to further re-program the tumor microenvironment by expressing immune-enhancer transgenes are ongoing.NCT02636036.© 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.