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IL-7 germline variant: setting the stage for immune-related adverse events.

ABSTRACT: Treatment with immune checkpoint inhibitors (ICIs) is frequently associated with immune-related adverse events (irAEs). A new study identified an interleukin 7 (IL-7) allelic variant-rs16906115-as a major risk factor for the development of ICI-associated irAEs. This association is of great significance as it indicates that germline genetic variants influence the occurrence of irAEs, thus opening a new avenue for identifying high-risk patients to enable better management of ICI therapy and associated irAEs.

SUBMITTER: Issaoui H

PROVIDER: S-EPMC9980302 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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IL-7 germline variant: setting the stage for immune-related adverse events.

Issaoui Hussein H Ricci Jean-Ehrland JE

Molecular oncology 20230224 3

Treatment with immune checkpoint inhibitors (ICIs) is frequently associated with immune-related adverse events (irAEs). A new study identified an interleukin 7 (IL-7) allelic variant-rs16906115-as a major risk factor for the development of ICI-associated irAEs. This association is of great significance as it indicates that germline genetic variants influence the occurrence of irAEs, thus opening a new avenue for identifying high-risk patients to enable better management of ICI therapy and associ ...[more]

PMID: 36748568

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Project description:IntroductionImmune checkpoint inhibitors (ICIs) can yield remarkable clinical responses in subsets of patients with solid tumors but can also often lead to immune-related adverse events (irAEs). Predictive features of clinically severe irAEs leading to cessation of ICIs have yet to be established. Using data from 1,327 patients with lung cancer treated with ICIs between 2009 and 2022 at four academic medical centers, we evaluated the association of a germline polygenic risk score for autoimmune disease and discontinuation of ICIs due to irAEs.MethodsUsing Cox proportional hazards model, we assessed the association between a polygenic risk score for autoimmune disease (PRSAD) and cessation of ICI therapy due to irAEs. All models were adjusted for age at diagnosis, sex, lung cancer histology, type of therapy, recruiting center, and the first 5 principal components. To further understand the differential effects of type of therapy and disease stage on the association between PRSAD and cessation of ICI due to irAEs, we conducted stratified logistic regression analysis by type of ICI therapy and disease stage.ResultsWe found an association between PRSAD and ICI cessation due to irAEs (HR per SD = 1.18, 95% CI = 1.02 - 1.37, P = 0.03). This association was particularly strong in patients who had ICI cessation due to irAEs within three months of therapy initiation (HR per SD = 1.38, 95% CI = 1.08 - 1.78, P = 0.01). Individuals in the top 20th percentile of PRSAD had 7.2% ICI discontinuation for irAEs by three months, compared to 3.9% discontinuation by three months among patients in the bottom 80th percentile (log-rank P = 0.02). In addition, among patients who received combination PD-1/PD-L1 and CTLA-4 inhibitor therapy, PRSAD had an OR per SD of 1.86 (95% CI = 1.08 - 3.51, P = 0.04).ConclusionsWe demonstrate an association between a polygenic risk score for autoimmune disease and early ICI discontinuation for irAEs, particularly among patients treated with combination ICI therapy. 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.

Dataset Information

IL-7 germline variant: setting the stage for immune-related adverse events.

Publications

IL-7 germline variant: setting the stage for immune-related adverse events.

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