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Background CX-801 is a masked PROBODY® cytokine therapeutic designed to deliver interferon-alpha2b (IFNα2b) selectively to the tumor microenvironment, aiming to minimize systemic toxicity while enhancing local immune activation. We report preliminary results demonstrating pharmacodynamic (PD) activity and pharmacokinetics (PK) of CX-801 from an ongoing, first-in-human, dose escalation study in patients with advanced melanoma.Methods CX-801 is currently being evaluated as monotherapy and in combination with pembrolizumab in patients with advanced melanoma ( NCT06462794). Key objectives include safety, PD, PK, and preliminary efficacy. PD assessments supporting CX-801 mechanism of action described herein were performed on tumor biopsies and peripheral blood samples collected from patients treated with monotherapy CX-801.Results PK analysis demonstrated dose-proportional exposure of CX-801, which remained predominantly in its intact (masked) form in circulation. CX-801 plasma half-life from the first three cohorts ranged from 4.9 - 11.5 days. Gene expression analysis of pre- and post-treatment tumor biopsies demonstrated consistently increased expression of interferon-stimulated genes (ISGs, n=5/5 patients). Elevated levels of CD8a+ T cells, NCR1+ natural killer (NK) cells, CD80+ dendritic cells, and increased granzyme B expression were observed, indicating activation of cytotoxic lymphocytes. Upregulation of immune checkpoint genes, including LAG3, PD-1, and PD-L1, was also observed, providing a rationale for evaluating the combination of CX-801 and pembrolizumab.Peripheral blood analyses revealed transient, dose-dependent increases in CD14+ monocytes, activated T cells, and serum CXCL10 levels after the first dose of CX-801. After the third dose of CX-801, the peripheral blood CXCL10 level remained unchanged, but there was an 8-fold elevation of tumor CXCL10 transcription, suggesting preferential CX-801 activity in the tumor versus the periphery.Conclusions Preliminary PD data indicate that CX-801 activates both innate and adaptive immune responses within the tumor microenvironment. These findings support the continued investigation of CX-801 as a novel immunotherapeutic agent for advanced solid tumors, including melanoma. Dose escalation of CX-801 as monotherapy and in combination with pembrolizumab is ongoing. Updated PD data will be provided at the conference.Trial Registration NCT06462794