Baseline peripheral blood activated-to-total CD8⁺ central memory T cell ratio to identify melanoma patients at high risk for severe toxicity but limited clinical benefit.

2568 Background: Immune-related adverse events (irAEs) represent a major clinical challenge that limits the usage of immune checkpoint blockade (ICB) for cancer therapy. The occurrence of irAEs often correlates with improved therapeutic response to ICB therapy, creating a therapeutic dilemma. Many known irAEs predictors correlate with treatment efficacy, further complicating clinical decision-making. Biomarkers that decouple severe irAEs risk from therapeutic benefit are thus urgently needed to guide clinical decision-making. Methods: We performed comprehensive peripheral blood immune profiling in two HCI (Huntsman Cancer Institute) clinical cohorts with 201 melanoma patients treated with ICB, analyzing 488-626 immune cell subsets and 1,463-2,926 plasma proteins at two timepoints: pretreatment and 3-6 weeks on therapy. Activated CD8+ T central memory (CD8Tcm) cells were defined by the expression of CD38, HLA-DR, or Ki67. Associations with severe irAEs, survival and treatment outcomes were evaluated across the largest test cohort composed of nine independent, multi-institutional clinical cohorts, two HCI cohorts, five Swiss cohorts, and two publicly available datasets. Results: Elevated pretreatment activated-to-total CD8+Tcm ratio robustly predicts severe irAEs. Patients with high versus low activated-to-total CD8+Tcm ratio showed two-fold or higher odds of developing severe irAEs across nine independent melanoma cohorts. Remarkably, this immune signature is associated with worse patient survival following ICB. These results suggest that there is a dedicated toxicity predictor in the peripheral blood. Incorporation of pretreatment plasma CXCL9 levels into a machine-learning regression model further improved irAEs predictive performance (mean AUC=0.78 across four independent cohorts). These baseline biomarkers outperformed previously reported irAEs predictors. Conclusions: The pretreatment activated-to-total CD8+Tcm ratio, alone or in combination with plasma CXCL9, identifies melanoma patients at high risk for severe irAEs who are not likely to respond to ICB treatment. This first of blood-based biomarker was tested and validated on many independent patients’ cohorts and will allow to select patients based on the risk stratification prior to treatment initiation.