Background: Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes and results in inhibition of B7-CTLA-4-mediated downregulation of T-cell activation. Both transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) have been shown to induce a peripheral immune response. The underlying hypothesis of this study is that the effect of anti-CTLA4 treatment can be enhanced by TACE or RFA in patients with HCC. Methods: Patients with HCC (Childs Pugh A/B7; Barcelona Clinic Liver Cancer Stage C; ECOG 0/1; post-sorafenib) are being enrolled in a pilot study of Tremelimumab at 2 dose levels (DL1 and DL2) until disease progression (irRECIST). Subtotal TACE or RFA is performed during study week 6 with DLT evaluation period encompassing first 8 weeks of study. Primary endpoint comprise safety and feasibility with secondary efficacy endpoints of time to tumor progression and overall survival. Exploratory objectives will evaluate changes in immune parameters in the peripheral blood of patients undergoing anti-CTLA4 therapy pre- and post-RFA or TACE. Results: 6 pts have been treated so far at DL1; M:F 4:2; Median age = 54(range 42-75); Cirrhosis present in 5pts. Hepatitis B/C/neg: 2/3/1. 3 pts received TACE, 3 underwent RFA. One patient experienced G3 hyperbilirubinemia. This occurred beyond the 8-week DLT period (5 weeks post-RFA) and was adjudicated as possibly related to treatment, but most likely related to concomitant medication. It followed a fluctuant course with subsequent resolution to G1/baseline. No other grade 3/4 treatment-related toxicities observed. No patient discontinued treatment due to toxicity. N=3 patients developed mild treatment-related rash requiring topical treatment. Conclusions: Tremelimumab in combination with TACE or RFA in patients with advanced HCC is feasible at the first of two planned dose levels with safety profile supporting continued development. Enrollment continues to the final planned dose level. Full safety data for both dose levels will be presented. Clinical trial information: NCT01853618.