与次甲基化剂结合是提高免疫检查点抑制剂治疗效果的一个有前途的策略。NIBIT-M4是一个Ⅰb期剂量递增试验，针对晚期黑色素瘤患者，研究了次甲基化剂瓜地辛与抗CTLA-4抗体伊匹单抗的联合治疗，遵循传统的3+3设计（临床试验登记号：NCT02608437）。患者每3周1次，从第0周开始，连续4周期皮下注射瓜地辛，剂量分别为30、45或60 mg/m^2/天；同时连续4周期静脉注射伊匹单抗，剂量为3 mg/kg。此前已经报道了安全性、耐受性和治疗最大耐受剂量的主要结果。本文报告了5年的临床结果，包括总生存率、无进展生存率、反应持续时间，以及对治疗前后肿瘤活检样本进行的综合多组学分析。经过至少45个月的随访，5年总生存率为28.9%，中位数反应持续时间为20.6个月。免疫调节内源性反转录病毒和其他重复元件的再表达以及瓜地辛的机械标记与治疗反应有关。将遗传免疫编辑指数与适应性免疫标志物相结合，将患者/病变划分为四个不同的亚组，并可区分5年总生存率和无进展生存率。这些结果表明，将遗传免疫编辑与适应性免疫激活相结合，对于通过表观遗传免疫调节在晚期黑色素瘤患者中实现长期临床效益是一个相关要求。© 2023. Springer Nature Limited.

Association with hypomethylating agents is a promising strategy to improve the efficacy of immune checkpoint inhibitors-based therapy. The NIBIT-M4 was a phase Ib, dose-escalation trial in patients with advanced melanoma of the hypomethylating agent guadecitabine combined with the anti-CTLA-4 antibody ipilimumab that followed a traditional 3 + 3 design (NCT02608437). Patients received guadecitabine 30, 45 or 60 mg/m2/day subcutaneously on days 1 to 5 every 3 weeks starting on week 0 for a total of four cycles, and ipilimumab 3 mg/kg intravenously starting on day 1 of week 1 every 3 weeks for a total of four cycles. Primary outcomes of safety, tolerability, and maximum tolerated dose of treatment were previously reported. Here we report the 5-year clinical outcome for the secondary endpoints of overall survival, progression free survival, and duration of response, and an exploratory integrated multi-omics analysis on pre- and on-treatment tumor biopsies. With a minimum follow-up of 45 months, the 5-year overall survival rate was 28.9% and the median duration of response was 20.6 months. Re-expression of immuno-modulatory endogenous retroviruses and of other repetitive elements, and a mechanistic signature of guadecitabine are associated with response. Integration of a genetic immunoediting index with an adaptive immunity signature stratifies patients/lesions into four distinct subsets and discriminates 5-year overall survival and progression free survival. These results suggest that coupling genetic immunoediting with activation of adaptive immunity is a relevant requisite for achieving long term clinical benefit by epigenetic immunomodulation in advanced melanoma patients.© 2023. Springer Nature Limited.