RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
放射治疗增强微卫星稳定结直肠癌和胰腺腺癌的免疫治疗反应：一项 II 期试验
英文原题：Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial.
查看英文原题
Radiation therapy enhances immunotherapy response in microsatellite stable colorectal and pancreatic adenocarcinoma in a phase II trial.
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中文摘要
克服微卫星稳定（MSS）结直肠癌（CRC）和胰腺导管腺癌（PDAC）对免疫检查点阻断的内在耐药性仍然具有挑战性。我们开展了一项单臂、非随机、II期试验（NCT03104439），联合放疗、ipilimumab和nivolumab治疗转移性MSS CRC（n = 40）和PDAC（n = 25）患者，其东部肿瘤协作组（ECOG）体能状态为0或1。主要终点为意向治疗分析下的疾病控制率（DCR）。CRC的DCR为25%（40例中10例；95%置信区间（CI），13-41%），PDAC的DCR为20%（25例中5例；95% CI，7-41%）。在符合方案分析中，定义为接受了放疗，CRC的DCR为37%（27例中10例；95% CI，19-58%），PDAC的DCR为29%（17例中5例；95% CI，10-56%）。治疗前活检显示所有样本的肿瘤突变负荷均较低，但在疾病控制的患者中自然杀伤（NK）细胞数量更多，且HERVK重复RNA表达更高。
本研究为在免疫治疗耐药癌症中联合放疗与免疫检查点阻断提供了概念验证。
展开英文摘要原文
Overcoming intrinsic resistance to immune checkpoint blockade for microsatellite stable (MSS) colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) remains challenging.
We conducted a single-arm, non-randomized, phase II trial (NCT03104439) combining radiation, ipilimumab and nivolumab to treat patients with metastatic MSS CRC (n = 40) and PDAC (n = 25) with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. The primary endpoint was disease control rate (DCR) by intention to treat. DCRs were 25% for CRC (ten of 40; 95% confidence interval (CI), 13-41%) and 20% for PDAC (five of 25; 95% CI, 7-41%).
In the per-protocol analysis, defined as receipt of radiation, DCR was 37% (ten of 27; 95% CI, 19-58%) in CRC and 29% (five of 17; 95% CI, 10-56%) in PDAC. Pretreatment biopsies revealed low tumor mutational burden for all samples but higher numbers of natural killer (NK) cells and expression of the HERVK repeat RNA in patients with disease control.
This study provides proof of concept of combining radiation with immune checkpoint blockade in immunotherapy-resistant cancers.
论文信息
- 作者
- Parikh AR、Szabolcs A、Allen JN、Clark JW、Wo JY、Raabe M、Thel H、Hoyos D
- 第一作者单位
- Department of Medicine, Division of Hematology & Oncology, Harvard Medical School, Boston, MA, USA.United States
- 通讯作者单位
- Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. tshong1@mgh.harvard.edu.United States
- 文献类型
- II 期临床试验 · 美国 NIH 资助研究 · 非美国政府资助研究
- 期刊
- Nature cancer2021 Nov
- 原文标识
- PubMed 35122060 · DOI 10.1038/s43018-021-00269-7
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