A study of using epigenetic modulators to enhance response to pembrolizumab (MK-3475) in microsatellite stable advanced colorectal cancer.

IF 5.7 2区 医学 Q1 Medicine
Marina Baretti, Adrian G Murphy, Marianna Zahurak, Nicole Gianino, Rose Parkinson, Rosalind Walker, Tamara Y Lopez-Vidal, Lei Zheng, Gary Rosner, Nita Ahuja, Schalper Kurt, Nilofer S Azad
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引用次数: 0

Abstract

Background: Approximately 95% of advanced colorectal cancer patients (CRC) have mismatch repair MMR-proficient (MMRp) tumors, which do not respond to PD1 blockade alone. Preclinical studies have shown that combined histone deacetylases (HDAC) and/or DNA methyltransferases (DNMT) inhibition can induce susceptibility to immune checkpoint therapy and inhibit tumor growth. We conducted a pilot trial evaluating PD-1 immune checkpoint inhibitor therapy in combination with DNMT and HDAC inhibitors in MMRp CRC. The study was designed with a biological endpoint of change in immune cell infiltration, to determine the optimal epigenetic combination that optimizes the tumor microenvironment. This trial was designed to test that hypothesis.

Results: From January 2016 to November 2018, 27 patients were enrolled with median age of 57 (range 40-69) years. Median progression-free survival and overall survival were 2.79 months and 9.17, respectively. One patient in Arm C achieved a durable partial response by RECIST criteria, lasting for approximately 19 months. The most common treatment-related hematological adverse events in all arms were anemia (62%), lymphopenia (54%) and thrombocytopenia (35%), and non-hematological AEs were anorexia (65%), nausea (77%), and vomiting (73%).

Conclusions: The combination of 5-azacitidine and romidepsin with pembrolizumab was safe and tolerable in patients with advanced MMRp CRC, but with a minimal activity. Further mechanistic investigations are needed to understand epigenetic-induced immunologic shift and to expand the potential applicability of checkpoint inhibitors in this setting.

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使用表观遗传调节剂增强微卫星稳定晚期结直肠癌患者对 pembrolizumab (MK-3475) 的反应的研究。
背景:约 95% 的晚期结直肠癌患者(CRC)患有错配修复 MMR-proficient(MMRp)肿瘤,这些肿瘤对单用 PD1 阻断剂无效。临床前研究表明,联合抑制组蛋白去乙酰化酶(HDAC)和/或DNA甲基转移酶(DNMT)可诱导对免疫检查点疗法的敏感性并抑制肿瘤生长。我们开展了一项试点试验,评估PD-1免疫检查点抑制剂与DNMT和HDAC抑制剂联合治疗MMRp CRC的效果。该研究以免疫细胞浸润变化为生物学终点,旨在确定优化肿瘤微环境的最佳表观遗传学组合。本试验旨在验证这一假设。结果:2016年1月至2018年11月,27名患者入组,中位年龄为57岁(40-69岁)。中位无进展生存期和总生存期分别为2.79个月和9.17个月。根据 RECIST 标准,C 组的一名患者获得了持久的部分反应,持续时间约为 19 个月。所有治疗组中最常见的治疗相关血液学不良事件为贫血(62%)、淋巴细胞减少(54%)和血小板减少(35%),非血液学不良事件为厌食(65%)、恶心(77%)和呕吐(73%):5-azacitidine和romidepsin与pembrolizumab联合治疗晚期MMRp CRC患者安全且可耐受,但活性极低。要了解表观遗传诱导的免疫学转变,并扩大检查点抑制剂在这种情况下的潜在适用性,还需要进一步的机理研究。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Clinical Epigenetics
Clinical Epigenetics Biochemistry, Genetics and Molecular Biology-Developmental Biology
CiteScore
8.90
自引率
5.30%
发文量
150
审稿时长
12 weeks
期刊介绍: Clinical Epigenetics, the official journal of the Clinical Epigenetics Society, is an open access, peer-reviewed journal that encompasses all aspects of epigenetic principles and mechanisms in relation to human disease, diagnosis and therapy. Clinical trials and research in disease model organisms are particularly welcome.
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