本文由小咖机器人翻译整理

期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02813-1

摘要内容如下：

染色质的表观遗传修饰，包括组蛋白乙酰化和肿瘤血管生成，在创造免疫抑制性肿瘤微环境中起着关键作用。在随机2期Capability-01试验中，我们研究了程序性细胞死亡蛋白-1（PD-1）单克隆抗体Sintilimab与组蛋白去乙酰化酶抑制剂（HDACi）西达本胺联合或不联合抗血管内皮生长因子（VEGF）单克隆抗体贝伐单抗治疗不可切除化疗难治性局部晚期或转移性微卫星稳定/熟练错配修复（MSS/PMMR）结直肠癌患者的潜在疗效。48名患者被随机分配到双联组（Sintilimab和西达本胺，n=23）或三联组（Sintilimab、西达本胺和贝伐单抗，n=25）。在整个研究人群中，18周无进展生存期（PFS）率（18WPFS率）的主要终点达标率为43.8%（21/48）。次要终点结果包括中位PFS为3.7个月，总缓解率为29.2%（14/48），疾病控制率为56.3%（27/48），中位缓解持续时间为12.0个月。中位总生存时间的次要终点不成熟。与双联组相比，三联组的预后显著改善，18WPFS率更高（64.0%对21.7%，p=0.003），总缓解率更高（44.0%对13.0%，p=0.027），中位无进展生存率更长（7.3个月对1.5个月，p=0.006）。在三联体和双联体中观察到的最常见的治疗中出现的不良事件包括蛋白尿、血小板减少症、中性粒细胞减少症、贫血、白细胞减少症和腹泻。有两例与治疗相关的死亡（肝衰竭和肺炎）。对来自患者的大量RNA测序数据的分析表明，三联体组合增强了CD8+T细胞浸润，导致更具免疫活性的肿瘤微环境。我们的研究表明，PD-1抗体、HDACi和VEGF抗体的组合可能是MSS/PMMR晚期结直肠癌患者的一种有前景的治疗方案。ClinicalTrials.gov注册：NCT04724239。

英文原文如下：

Abstracts

Epigenetic modifications of chromatin, including histone acetylation, and tumor angiogenesis play pivotal roles in creating an immunosuppressive tumor microenvironment. In the randomized phase 2 CAPability-01 trial, we investigated the potential efficacy of combining the programmed cell death protein-1 (PD-1) monoclonal antibody sintilimab with the histone deacetylase inhibitor (HDACi) chidamide with or without the anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab in patients with unresectable chemotherapy-refractory locally advanced or metastatic microsatellite stable/proficient mismatch repair (MSS/pMMR) colorectal cancer. Forty-eight patients were randomly assigned to either the doublet arm (sintilimab and chidamide, n = 23) or the triplet arm (sintilimab, chidamide and bevacizumab, n = 25). The primary endpoint of progression-free survival (PFS) rate at 18 weeks (18wPFS rate) was met with a rate of 43.8% (21 of 48) for the entire study population. Secondary endpoint results include a median PFS of 3.7 months, an overall response rate of 29.2% (14 of 48), a disease control rate of 56.3% (27 of 48) and a median duration of response of 12.0 months. The secondary endpoint of median overall survival time was not mature. The triplet arm exhibited significantly improved outcomes compared to the doublet arm, with a greater 18wPFS rate (64.0% versus 21.7%, P = 0.003), higher overall response rate (44.0% versus 13.0%, P = 0.027) and longer median PFS rate (7.3 months versus 1.5 months, P = 0.006). The most common treatment-emergent adverse events observed in both the triplet and doublet arms included proteinuria, thrombocytopenia, neutropenia, anemia, leukopenia and diarrhea. There were two treatment-related fatalities (hepatic failure and pneumonitis). Analysis of bulk RNA sequencing data from the patients suggested that the triplet combination enhanced CD8+ T cell infiltration, resulting in a more immunologically active tumor microenvironment. Our study suggests that the combination of a PD-1 antibody, an HDACi, and a VEGF antibody could be a promising treatment regimen for patients with MSS/pMMR advanced colorectal cancer. ClinicalTrials.gov registration: NCT04724239 .

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