B-384 Genetic Variations Predict Severe Immunotherapy-related Adverse Events for PD-1/PD-L1 Inhibitors

Abstract

Abstract Background PD-1/PD-L1 inhibitors have brought remarkable benefits but can cause profound immune-related adverse events (irAEs), especially life-threatening toxicities. The host immunogenetic background is likely to play a role in irAE susceptibility. Here, we identified the variants that could predict severe irAEs in patients with cancer. Methods Patients with solid tumors receiving PD-1/PD-L1 blockade were recruited and followed up. Genes considered pivotal contributors to tumor-immunity and autoimmune diseases were screened out via Protein-Protein Interaction network and Cytoscape. Consequently, thirty-nine variants in eighteen genes were genotyped using the multiplex genotyping assay. Association analysis between those variants and severe irAEs (G3-G5 grades) as well as irAEs-free survival was performed. Results Two immunogenetic variants as predictors of severe irAEs were identified. The A allele of ADAD1 rs17388568 (OR = 2.599, 95% CI = 1.355–4.983, P = 0.003) increased the risk of severe irAEs, while the G allele of IL6 rs1800796 (OR = 0.425, 95% CI = 0.205–0.881, P = 0.018) protected patients from severe irAEs. In multivariate Cox regression analysis, ADAD1 rs17388568 (AA vs AG or GG: HR = 0.11, 95% CI = 0.025–0.49, P = 0.004) and IL6 rs1800796 (GG or GC vs CC: HR = 3.10, 95% CI = 1.315–7.29, P = 0.01) were also independent variables for severe irAEs-free survival. Conclusion We identified two immunogenetic polymorphisms associated with severe irAEs in PD-1/PD-L1 blockade-treated tumor patients at the first time, and they may serve as promising predictive biomarkers.