medwireNews: A variant of the interleukin (IL)7 gene is associated with an increased risk of immune-related adverse events (irAEs) in people with cancer receiving immune checkpoint inhibitor (ICI) therapy, suggests research.
The association was observed in a pancancer cohort comprising patients across 12 tumour types and confirmed in a separate cohort of melanoma patients. Both studies are published in Nature Medicine.
Caroline Robert (Gustave Roussy, Villejuif, France) and fellow authors of an accompanying commentary say that these results “provide a strong incentive to explore innovative RNA-based therapies, and more specifically those targeting RNA splicing, in order to modulate IL7 expression in B cells and favorably control the benefit/risk balance of existing ICI treatments”.
They continue: “Future studies should aim to determine the basis of the prognostic role of IL-7 in cancer and explore therapeutic tools for controlling IL7 expression to modulate this immune gradient.”
The investigators of the first study identified 1751 individuals of European ancestry who received ICIs for cancer at a US tertiary institution between 2013 and 2020. Participants were aged an average of 63 years and the majority (88.4%) received single-agent PD-1 or PD-L1 inhibitor therapy. The most common tumour type in the cohort was non-small-cell lung cancer, in 30.8%, followed by melanoma, in 13.8%.
Around a fifth (19.4%) of the cohort experienced all-grade irAEs, while 14.8% had a high-grade irAE, defined as an event of grade 3 or worse.
A genome-wide association study identified significant correlations for all-grade, but not high-grade irAEs, report Alexander Gusev (Dana-Farber Cancer Institute, Boston, Massachusetts, USA) and colleagues.
Specifically, the rs16906115 single nucleotide polymorphism (SNP) in an intron of IL7 on chromosome 8q21, the rs75824728 SNP in an intron of IL22RA1 on chromosome 1p36 and the rs113861051 SNP on chromosome 4p15 were significantly associated with an increased risk of all-grade irAEs, with respective hazard ratios (HRs) of 2.0, 1.9 and 2.0.
The IL7 rs16906115 variant was also significantly associated with irAEs in an independent pancancer cohort of 265 ICI-treated patients with severe irAEs requiring hospitalisation (HR=2.5), and there was a trend towards significance in a third cohort comprising 2275 European participants of 12 previously reported clinical trials of the PD-L1 inhibitor atezolizumab who developed irAEs of grade 2–5 (HR=1.2).
For the second study, Benjamin Fairfax (University of Oxford, UK) and co-workers drew on the Oxford Radcliffe Biobank to identify 214 patients who received ICIs for melanoma, either in the metastatic or adjuvant setting, between 2015 and 2021.
The risk of developing high-grade irAEs requiring corticosteroids before the fifth cycle of treatment was significantly higher for patients carrying one or two versus no copies of the IL7 rs16906115 risk variant, with an odds ratio (OR) of 2.24.
Individuals who received single-agent anti-PD-1 treatment had an especially pronounced risk of high-grade irAEs in the presence of the IL7 variant, at ORs of 6.0 and 4.4 for irAEs requiring steroids by the fifth cycle or at any timepoint during treatment, respectively. By contrast, the ORs were nonsignificant for patients treated with a combination of PD-1 and CTLA-4 inhibitors.
Furthermore, analysis of The Cancer Genome Atlas data suggested that carriage of this variant allele was also associated with improved survival outcomes, “inferring that, in addition to predisposing patients to [ICI] toxicity, B cell IL7 plays a role in the natural history of melanoma”, which “further highlights the potential therapeutic importance of this pathway”, the researchers comment.
They conclude that the study “delineates a key role for IL-7 in response to [ICIs], revitalizing previous proposals for incorporating this molecule as a potential adjunct to immunotherapy strategies.”
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