Background: Metastatic vRCC are aggressive tumors with poor prognosis. Our phase 2 trial of AB in vRCC showed a response rate of 33%. We investigated on-therapy changes in circulating immune cells and cytokines and their association with outcomes. Methods: Blood was collected at baseline (C1D1) and on-therapy (C3D1). Peripheral blood mononuclear cells were analyzed for cell type, expression of immune checkpoints, markers of activation, proliferation and function using flow cytometry; circulating cytokines by multiplex immunoassay. Relationship with progression-free (PFS) and overall survival (OS) was assessed by cox regression models. Results: Baseline and on-therapy samples were collected from all 60 patients. High baseline levels of immunosuppressive cytokines IL1α, IL6, CCL4 and IL13, as well as high baseline levels of CD4+ lymphocytes expressing CD69, were associated with inferior PFS and OS (Table). However, a decline in these markers on-therapy was not predictive of outcomes. On-therapy assessments showed an increase in the IFN-γ inducible cytokine CXCL10 (p<0.0001) as well as an increase in VEGF-A (p<0.0001) consistent with induction of antitumor immunity and inhibition of angiogenesis. A decrease in PD-L1 expression on circulating CD8+ lymphocytes was associated with shorter PFS and OS (Table), suggesting a potential resistance mechanism. Conclusions: High baseline levels of immunosuppressive cytokines and CD4+ CD69+ lymphocytes portended worse survival in patients treated with AB. Early changes in PD-L1 expression on circulating CD8+ lymphocytes may inform resistance to therapy. Correlation of circulating and tissue-based biomarkers is ongoing. Clinical trial information: NCT02724878