1069P Potential biomarkers for predicting severe immune-related adverse events during checkpoint immunotherapy: T Cell receptor and whole exome sequencing findings from a prospective multicenter study

Grade 3/4 immune-related adverse events (severe irAEs), caused by anti-PD-1/PD-L1 antibodies, can lead to fulminant and even fatal consequences. However, the identification of biomarkers for irAEs prediction is lacking. Previous studies have suggested that germline mutations and T-cell receptor (TCR) diversity are associated with the development of irAEs during cancer immunotherapy. Here, our study aims to explore promising biomarkers for predicting severe irAEs. Patients who received immune checkpoint inhibitors (ICIs) treatment between November 2021 and December 2022 were enrolled in a study with follow-up. Blood samples were collected at baseline and from those with severe irAEs during or after treatment. Blood samples underwent whole exome sequencing and TCR sequencing. Germline mutations were compared between severe irAEs and non-severe irAEs groups, with additional TCR analysis including diversity index and cluster analysis. The study enrolled 128 patients, among whom 12 (9.38%) developed serious irAEs. Germline mutations in 10 immune-related genes (MMEL1, MDM4, GPR35, LPP, BACH2, EGFR, JAK2, PTEN, SMAD3, TYK2) were significantly different between severe and non-severe irAEs groups (p < 0.05). TCR sequencing analysis revealed that 3 motifs in the severe irAEs group and 7 motifs in the non-severe irAEs group were also significantly different (p < 0.05). A PLS-DA analysis combining biomarkers, genes, and motifs successfully distinguished between the two groups. Additionally, we observed a significant decline in CDR3 counts from baseline to post-severe irAEs in TCR. Study results indicated that germline mutations and changes in TCR characteristics may predict severe irAEs in cancer immunotherapy, emphasizing the need for further research and personalized management of these adverse events.