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 Clinical Epigenetics Pub Date : 2023-04-29 DOI:10.1186/s13148-023-01485-x
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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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。
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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.
期刊最新文献
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