Department of Epigenetics, Van Andel Institute, Grand Rapids, Michigan.
Pathology and Biorepository Core, Van Andel Institute, Grand Rapids, Michigan.
Clin Cancer Res. 2023 Jun 1;29(11):2052-2065. doi: 10.1158/1078-0432.CCR-22-3642.
On the basis of preclinical evidence of epigenetic contribution to sensitivity and resistance to immune checkpoint inhibitors (ICI), we hypothesized that guadecitabine (hypomethylating agent) and atezolizumab [anti-programmed cell death ligand 1 (PD-L1)] together would potentiate a clinical response in patients with metastatic urothelial carcinoma (UC) unresponsive to initial immune checkpoint blockade therapy.
We designed a single arm phase II study (NCT03179943) with a safety run-in to identify the recommended phase II dose of the combination therapy of guadecitabine and atezolizumab. Patients with recurrent/advanced UC who had previously progressed on ICI therapy with programmed cell death protein 1 or PD-L1 targeting agents were eligible. Preplanned correlative analysis was performed to characterize peripheral immune dynamics and global DNA methylation, transcriptome, and immune infiltration dynamics of patient tumors.
Safety run-in enrolled 6 patients and phase II enrolled 15 patients before the trial was closed for futility. No dose-limiting toxicity was observed. Four patients, with best response of stable disease (SD), exhibited extended tumor control (8-11 months) and survival (>14 months). Correlative analysis revealed lack of DNA demethylation in tumors after 2 cycles of treatment. Increased peripheral immune activation and immune infiltration in tumors after treatment correlated with progression-free survival and SD. Furthermore, high IL6 and IL8 levels in the patients' plasma was associated with short survival.
No RECIST responses were observed after combination therapy in this trial. Although we could not detect the anticipated tumor-intrinsic effects of guadecitabine, the addition of hypomethylating agent to ICI therapy induced immune activation in a few patients, which associated with longer patient survival.
基于表观遗传在免疫检查点抑制剂（ICI）敏感性和耐药性中的作用的临床前证据，我们假设地西他滨（去甲基化剂）和阿替利珠单抗[抗程序性死亡配体 1（PD-L1）]联合治疗可能会增强对初始免疫检查点阻断治疗无反应的转移性尿路上皮癌（UC）患者的临床反应。
我们设计了一项单臂 II 期研究（NCT03179943），其中包括安全性入组，以确定地西他滨和阿替利珠单抗联合治疗的推荐 II 期剂量。符合条件的患者为既往接受 PD-1 或 PD-L1 靶向药物的 ICI 治疗后复发/进展的复发性/晚期 UC 患者。进行了预先计划的相关性分析，以表征患者肿瘤的外周免疫动态、全基因组甲基化、转录组和免疫浸润动态。
安全性入组纳入了 6 例患者，II 期入组了 15 例患者，然后该试验因无效而关闭。未观察到剂量限制毒性。4 例患者的最佳反应为疾病稳定（SD），表现出延长的肿瘤控制（8-11 个月）和生存（>14 个月）。相关性分析显示治疗 2 周期后肿瘤中无 DNA 去甲基化。治疗后外周免疫激活和肿瘤免疫浸润增加与无进展生存期和 SD 相关。此外，患者血浆中高 IL6 和 IL8 水平与较短的生存时间相关。
该试验联合治疗后未观察到 RECIST 反应。尽管我们未能检测到地西他滨预期的肿瘤内在作用，但在 ICI 治疗中加入去甲基化剂可诱导少数患者的免疫激活，与患者的生存时间延长相关。
