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 which may enhance the effect of anti-CTLA4 treatment in patients with advanced HCC. Methods: Patients with HCC [Childs Pugh A/B7; Barcelona Clinic Liver Cancer Stage B/C; ECOG 0/1; sorafenib refractory/intolerant (BCLC stage C only)] were enrolled in a pilot study of Tremelimumab at 2 dose levels (DL1 and DL2) until PD (irRECIST). Subtotal TACE or RFA was performed during study week 6 with DLT evaluation period encompassing first 8 weeks of study. Tumor biopsy at baseline and at time of RF/TACE. Results: 20 pts were enrolled with N = 18 evaluable for primary endpoint. Baseline characteristics: M:F 15:3; Median age = 54(range 42-76); Cirrhosis present in 13pts; BCLC Stage B/C: 4/14; Hepatitis B/C/neg: 4/10/4. 8 pts received TACE, 10 underwent RFA during week 6 of tremelimumab therapy. No DLT encountered. Most common toxicity was pruritus. One patient developed pulmonitis and was taken off study but remains disease-free at 16months. Of N = 10 pts evaluable for response outside of TACE/RFA-treated lesion 4 (40%) achieved confirmed partial responses. 5 of 7 pts with quantifiable HCV experienced a marked reduction in viral load. 6-week tumor biopsies showed immune cell infiltration on all evaluable patients. Median PFS for the study population (N = 17) was 7.4months. Conclusions: Tremelimumab in combination with subtotal TACE or RFA in patients with advanced HCC is safe and feasible. Obtaining tumor biopsies at baseline and at the time of RFA/TACE is safe. Evidence of immune cell infiltration was seen on evaluable patients. Encouraging clinical activity has been seen with objective confirmed responses, TTP 7.4m and possibly surrogate reductions in HCV viral load. Clinical trial information: NCT01853618