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
{"title":"Germline prediction of immune checkpoint inhibitor discontinuation for immune-related adverse events.","authors":"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","doi":"10.1136/jitc-2024-011273","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>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.</p><p><strong>Methods: </strong>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 (PRS<sub>AD</sub>) in the general population and validated it in the All of Us. We then assessed the association between PRS<sub>AD</sub> 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 PRS<sub>AD</sub> and cessation of ICI due to irAEs, we conducted a stratified analysis by type of ICI therapy.</p><p><strong>Results: </strong>Using a competing risk model, we found an association between PRS<sub>AD</sub> 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 PRS<sub>AD</sub> 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 PRS<sub>AD</sub> genetic risk (top quintile) versus 3 of 21 patients (14.3%) with low PRS<sub>AD</sub> genetic risk (bottom quintile).</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 3","pages":""},"PeriodicalIF":10.3000,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11956315/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal for Immunotherapy of Cancer","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/jitc-2024-011273","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
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.

求助全文
约1分钟内获得全文 求助全文
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.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信