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评估 FcγRIIIA 单核苷酸多态性对晚期胃食管腺癌患者 IgG1 单克隆抗体疗效的影响

英文原题：Assessment of the impact of FcγRIIIA single-nucleotide polymorphisms on the efficacy of IgG1 monoclonal antibodies in patients with advanced gastroesophageal adenocarcinoma.

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Assessment of the impact of FcγRIIIA single-nucleotide polymorphisms on the efficacy of IgG1 monoclonal antibodies in patients with advanced gastroesophageal adenocarcinoma.

PubMed 2023/11/27（内容时间） ESMO Gastrointest Oncol Q4 · IF 1.7（JCR 2025）

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技术：NK 细胞地区：美国
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研究概要

我们报告了首个真实世界数据，分析 FcγRIIIA 基因型如何影响 aGEA 中 mAb 应答。其他显著的分子/临床变量影响 mAb 应答。结果重申了 ADCC 在 aGEA 中的重要性。需要进一步工作来阐明为何某些患者对 mAb 是“卓越应答者”。

研究思路结论见上方概要

背景

免疫球蛋白G1（IgG1）单克隆抗体（mAbs），如曲妥珠单抗和雷莫芦单抗，被用于晚期胃食管腺癌（aGEA）。mAb治疗效果的重要机制是通过抗体依赖性细胞介导的细胞毒性（ADCC）被自然杀伤（NK）细胞参与。NK细胞上的某些高亲和力FcγRIIIA受体变异体（在氨基酸158位以苯丙氨酸替代缬氨酸）增强了片段C受体对IgG1片段结晶（Fc）域的亲和力，导致更强的mAb抗肿瘤效果。在氨基酸158位点可能有三种基因型（V/V、V/F和F/F）。我们试图确定FcγRIIIA基因型是否影响aGEA患者对mAbs的真实世界反应。

方法

PANGEA试验（NCT02213289）中74/80例患者有全血样本可用。我们在本机构确定了另外35例接受mAbs治疗的aGEA患者（“非PANGEA患者”）。利用PCR，我们确定了患者FcγRIIIA基因第158位氨基酸的异型。我们计算/比较了三种FcγRIIIA基因型之间的3年总生存期（OS）率。

结果

最高亲和力（V/V）和杂合（V/F）变异分别存在于18%（20/109）和50%（55/109）的患者中。在PANGEA患者中，三种基因型的中位OS相似。在非PANGEA患者中，与低亲和力患者相比，高亲和力患者（即V/V或V/F患者）有生存期延长的趋势（mOS 43.4个月对23.1个月，P = 0.07）；在非PANGEA患者中，与低亲和力患者相比，高亲和力患者的36个月OS显著更高（50%对13%，P = 0.04）。非F/F患者对mAbs有异常应答。

展开英文摘要原文
BACKGROUND

Immunoglobulin G1 (IgG1) monoclonal antibodies (mAbs), such as trastuzumab and ramucirumab, are utilized in advanced gastroesophageal adenocarcinoma (aGEA). The important mechanism of mAb therapeutic effect is engagement by natural killer (NK) cells via antibody-dependent cellular cytotoxicity (ADCC). Certain high-affinity FcγRIIIA receptor variants (substituting phenylalanine for valine at amino acid 158) on NK cells enhance fragment C receptor's affinity for the IgG1 fragment crystallizable (Fc) domain, leading to stronger mAb antitumor effects. Three genotypes are possible at amino acid 158 position (V/V, V/F, and F/F). We attempted to determine whether FcγRIIIA genotype affected real-world responses to mAbs in aGEA patients.

PATIENTS AND METHODS

Whole blood was available from 74/80 patients in the PANGEA trial (NCT02213289). We identified 35 additional aGEA patients ('non-PANGEA patients') treated with mAbs at our institution. Utilizing PCR, we determined patient allotypes at amino acid position 158 for the FcγRIIIA gene. We calculated/compared 3-year overall survival (OS) rates between the three FcγRIIIA genotypes.

RESULTS

The highest affinity (V/V) and heterozygotic (V/F) variants were present in 18% (20/109) and 50% (55/109) of patients, respectively. Median OS was similar across all three genotypes in PANGEA patients. In non-PANGEA patients, there was a trend towards increased survival in higher-affinity patients (i.e. V/V or V/F patients) compared to low-affinity patients (mOS 43.4 versus 23.1 months, P = 0.07); in non-PANGEA patients, higher-affinity patients had significantly higher 36-month OS (50% versus 13%, P = 0.04) compared to low-affinity patients. Non-F/F patients had an exceptional response to mAbs.

CONCLUSIONS

We report the first real-world data analyzing how FcγRIIIA genotype impacts mAb response in aGEA. Other significant molecular/clinical variables affect mAb responses. Results reiterate the importance of ADCC in aGEA. Further work is needed to elucidate why certain patients are 'exceptional responders' to mAb.

论文信息

作者
Serritella AV、Grewal NKS、Peterson B、Arndt K、Gaudio DD、Liu P、Shergill A、Polite B
第一作者单位
Section of Hematology/Oncology, Department of Medicine, Robert H Lurie Comprehensive Cancer Center, Northwestern Feinberg School of Medicine, Chicago.United States
通讯作者单位
Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center and Biological Sciences, Chicago.United States
期刊
ESMO gastrointestinal oncology2023 Dec
原文标识
PubMed 41647730　·　DOI 10.1016/j.esmogo.2023.08.011

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