Investigating peripheral blood biomarkers of immune checkpoint inhibitor associated fatigue.

• DOI: 10.1200/jco.2024.42.16_suppl.2571
• Publication Date: 2024-06-14T13:46:55Z
• Authors: Howard Liu Li; Soren Charmsaz; Stephanie Leigh A...; Madelena Brancati; Aanika Warner; Kabeer Munjal; Hua-Ling Tsai; Nicole E. Gross; Christopher Thoburn; Evan J. Lipson; Yasser Ged; Rachel Garonce-He...; Sanjay Bansal; Laura Tang; Elizabeth M. Jaffee; G Scott Chandler; Rajat Mohindra; Won Jin Ho; Mark Yarchoan; Chester Kao
• Keywords: 03 medical and health sciences; 0302 clinical medicine

2571 Background: Fatigue is the most common side effect of immune checkpoint inhibitor (ICI) therapy. Despite its prevalence, the mechanisms underlying ICI-associated fatigue are poorly understood. In this study, we characterized dynamic changes in peripheral immune cell populations and cytokines to identify biomarkers and mechanisms of ICI-associated fatigue. Methods: We prospectively collected clinical data and blood samples from patients with solid tumors at a single institution who received ICIs between July 2021 and November 2023. Blood samples were collected at baseline, early-on-treatment (month 1-2), and later-on-treatment (month 4-6). Patients were contacted on-treatment to query for worsening of fatigue compared to treatment baseline. We analyzed peripheral lymphocyte populations by Cytometry by Time-of-Flight (CyTOF) and peripheral levels of 39 cytokines with Luminex multiplex assay. Tumor response was characterized by RECIST v1.1. False discovery rate (FDR) was used for multi-testing adjustment. Results: 53 patients received ICI therapy and had fatigue assessment performed. Thirty-one patients (58.5%) reported worsening fatigue, and 22 (41.5%) did not. In patients with worsened fatigue, a cluster of cytotoxic effector CD8+CD28+TIGIT+ T-cells was significantly increased from baseline to early-on-treatment (Wilcoxon Signed-rank Test FDR adjusted p<.05). Early-on-treatment fold changes in Type 1 cytokines (IFN-gamma, IL-2, IL-12) were increased in patients with worsened fatigue compared to patients with no fatigue (Wilcoxon Rank-sum Test unadjusted p<.05; Table). There was no association between increase in fatigue and objective response to ICI therapy, although numerically high rates of fatigue were observed both in patients experiencing disease progression as well as complete responses. After excluding patients with tumor progression to account for tumor-related fatigue, early-on-treatment fold changes in IL-2 and IL-12 were still increased in worsened fatigued compared to non-fatigued patients (unadjusted p<.05). However, in patients with disease progression, changes in Type 1 cytokines were not associated with worsening fatigue. Conclusions: In a pan-tumor cohort treated with ICIs, increases in a cluster of cytotoxic effector CD8+ T cells in parallel with related Type 1 cytokines were associated with fatigue, implicating fatigue as a marker of immune activation in this population. [Table: see text]