Abstract 1185: Novel association of an autoimmune-related axis and anti-CTLA-4-based toxicities in adjuvant immunotherapy-treated melanoma patients
Authors: Monson Kelsey R. , Ferguson Robert , Handzlik Joanna , Xiong Jiahan , Dagayev Sasha , Morales Leah , Chat Vylyny , Bunis Anabelle , Sreenivasaiah Chaitra , Dolfi Sonia , Tenney Daniel , Osman Iman , Weber Jeffrey , Kirchhoff Tomas 
Published: March 2024

Abstract
Intro: Immune checkpoint inhibition (ICI) for metastatic unresectable melanoma has markedly improved survival, and has shown benefit as adjuvant (AT) and neoadjuvant (NAT) therapy. Although ICI treatments confer survival benefit, they frequently induce immune-related adverse events (irAEs), which are a substantial clinical problem, particularly in AT/NAT, where ICI is used in less advanced disease to prevent recurrence. As such, the biomarkers predicting irAE risk, in particular in AT/NAT, are urgently needed to improve patient outcomes.
Methods: We assessed RNA from pre-treatment peripheral CD4+ and CD8+ T cells from adjuvant clinical trial patients (CheckMate-915; n=212 patients) treated with Nivolumab (n=130) or Ipilimumab/Nivolumab (Combo) (n=82). We performed RNA-seq differential expression analysis to identify baseline differences in the immune profiles of patients with no/mild toxicity (grade 0-2) versus severe toxicity (grade 3-5).
Results: Gene ontology analysis of the differentially expressed genes (DEGs) among those with severe toxicity reveals significant enrichment of immune-related pathways (IL-2, IFN-gamma, T-cell receptors, Toll-like receptors). These are shared among cell types (CD4+/CD8+) and between treatments (Nivo/Combo). From predicted DEG protein-protein interactions, we identified a treatment- and cell-type-specific expression signature associated with irAE development in CD4+ cells from Combo-treated patients. This signature, involving genes in the spleen tyrosine kinase (SYK) pathway, correctly predicts severe irAE patients with 73% accuracy (chi-squared p-value=0.001). The signature also identifies patients with mild to moderate irAEs in organ systems previously found in autoimmune traits to be associated with SYK upregulation (including skin, GI, liver, and pancreas), with 96% of all predicted patients experiencing at least one of these SYK-related toxicities, and 79% experiencing two or more. Importantly, the signature is not associated with disease recurrence (p=0.79).
Conclusions: We have identified baseline expression differences in key immune pathways in peripheral T cells from ICI-treated patients with severe irAEs, and defined an SYK-related gene signature correctly identifying over half of severe irAE patients in the Combo-treated cohort. This finding aligns with our previous work linking anti-CTLA-4 irAEs with a germline variant associated with high SYK expression. This gene signature may not only serve as a baseline biomarker of severe irAEs, but it may also help guide treatment decisions, reducing toxicity while retaining efficacy, which will be particularly important in the adjuvant setting.
Citation Format: Kelsey R. Monson, Robert Ferguson, Joanna Handzlik, Jiahan Xiong, Sasha Dagayev, Leah Morales, Vylyny Chat, Anabelle Bunis, Chaitra Sreenivasaiah, Sonia Dolfi, Daniel Tenney, Iman Osman, Jeffrey Weber, Tomas Kirchhoff. Novel association of an autoimmune-related axis and anti-CTLA-4-based toxicities in adjuvant immunotherapy-treated melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1185.