Germline prediction of immune checkpoint inhibitor discontinuation for immune-related adverse events.

IF 10.3 1区 医学 Q1 IMMUNOLOGY
Pooja Middha, Rohit Thummalapalli, Zoe Quandt, Karmugi Balaratnam, Eduardo Cardenas, Christina J Falcon, Princess Margaret Lung Group, Matthew A Gubens, Scott Huntsman, Khaleeq Khan, Min Li, Christine M Lovly, Devalben Patel, Luna Jia Zhan, Geoffrey Liu, Melinda C Aldrich, Adam Schoenfeld, Elad Ziv
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引用次数: 0

Abstract

Introduction: Immune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors, but they also commonly cause immune-related adverse events (irAEs). The predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Given the similarities between irAEs and autoimmune diseases, we sought to investigate the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs.

Methods: The Genetics of immune-related adverse events and Response to Immunotherapy (GeRI) cohort comprises 1302 patients with non-small cell lung cancer (NSCLC) who received ICI therapy between 2009 and 2022 at four academic medical centers. We used a published polygenic risk score for autoimmune diseases (PRSAD) in the general population and validated it in the All of Us. We then assessed the association between PRSAD and cessation of ICI therapy due to irAEs in the GeRI cohort, using cause-specific and Fine-Gray subdistribution hazard models. To further understand the differential effects of type of therapy on the association between PRSAD and cessation of ICI due to irAEs, we conducted a stratified analysis by type of ICI therapy.

Results: Using a competing risk model, we found an association between PRSAD and ICI cessation due to irAEs (HR per SD=1.24, p=0.004). This association was particularly strong in patients who had ICI cessation due to irAEs within 3 months of therapy initiation (HR per SD=1.40, p=0.005). Individuals in the top quintile of PRSAD had 4.8% ICI discontinuation for irAEs by 3 months, compared with 2% discontinuation by 3 months among patients in the bottom quintile (log-rank p=0.03). In addition, among patients who received combination programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and cytotoxic T-lymphocyte associated protein 4 (CTLA4) inhibitors, ICI discontinuation for irAEs by 3 months occurred in 4 of the 13 patients (30.8%) with high PRSAD genetic risk (top quintile) versus 3 of 21 patients (14.3%) with low PRSAD genetic risk (bottom quintile).

Conclusions: We demonstrate an association between a polygenic risk score for autoimmune disease and early ICI discontinuation for irAEs. Our results suggest that germline genetics may be used as an adjunctive tool for risk stratification around ICI clinical decision-making in solid tumor oncology.

免疫检查点抑制剂停药对免疫相关不良事件的种系预测。
免疫检查点抑制剂(ICIs)可以在实体瘤患者亚群中产生显着的临床反应,但它们也通常引起免疫相关不良事件(irAEs)。临床严重irae导致ICIs停止的预测特征尚未确定。考虑到irAEs与自身免疫性疾病之间的相似性,我们试图调查自身免疫性疾病的种系多基因风险评分与irAEs导致的ICIs中断之间的关系。方法:免疫相关不良事件的遗传学和对免疫治疗的反应(GeRI)队列包括2009年至2022年间在四个学术医疗中心接受ICI治疗的1302例非小细胞肺癌(NSCLC)患者。我们在普通人群中使用了已发表的自身免疫性疾病多基因风险评分(PRSAD),并在我们所有人身上进行了验证。然后,我们使用病因特异性和Fine-Gray亚分布风险模型,评估了PRSAD与GeRI队列中因irae而停止ICI治疗之间的关系。为了进一步了解不同治疗类型对PRSAD与irAEs所致ICI停止之间关系的不同影响,我们按ICI治疗类型进行了分层分析。结果:使用竞争风险模型,我们发现PRSAD与因irAEs引起的ICI停止之间存在关联(HR / SD=1.24, p=0.004)。这种关联在治疗开始3个月内因irae而停止ICI的患者中尤为明显(HR / SD=1.40, p=0.005)。在PRSAD的前五分之一的患者中,有4.8%的患者在3个月内停止使用化疗药物,而在后五分之一的患者中,有2%的患者在3个月内停止使用化疗药物(log-rank p=0.03)。此外,在接受程序性细胞死亡蛋白-1 (PD-1)/程序性死亡配体1 (PD-L1)抑制剂和细胞毒性t淋巴细胞相关蛋白4 (CTLA4)抑制剂联合治疗的患者中,13名高PRSAD遗传风险患者中有4名(30.8%)因irAEs停药3个月,而21名低PRSAD遗传风险患者中有3名(14.3%)。结论:我们证明了自身免疫性疾病的多基因风险评分与irAEs患者早期停止ICI之间的关联。我们的研究结果表明,生殖系遗传学可以作为一种辅助工具,在实体肿瘤肿瘤的ICI临床决策中进行风险分层。
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
Journal for Immunotherapy of Cancer
Journal for Immunotherapy of Cancer Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
17.70
自引率
4.60%
发文量
522
审稿时长
18 weeks
期刊介绍: The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.
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