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. Transcatheter arterial chemoembolization (TACE), radiofrequency (RFA) and cryoablation (CA) have been shown to induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment. Methods: Patients with HCC [Childs Pugh A/B7; BCLC B/C; ECOG 0/1; post-sorafenib (BCLC stage C only)] or refractory BTC were enrolled in a study of Tremelimumab combined with subtotal TACE, RFA or CA performed on week 6. All BTC patients received RFA in combination with tremelimumab. Tumor biopsies were performed at baseline and at time of RF/TACE. Results: 41 pts enrolled (32 HCC, 9 BTC). Characteristics: M:F 31:10; Median age 54(range 42-76); In HCC pts cirrhosis present in 22pts, BCLC Stage B/C: 9/23; Hepatitis B/C/neg: 5/18/9. 14 pts received TACE, 19 underwent RFA (inc all 9 BTC pts), 5 CA during week 6 of tremelimumab therapy. 3 pts did not receive an ablative procedure (due to PD). No DLT encountered. Most common toxicity was pruritus. Of N = 17 pts evaluable for response outside of TACE/RFA-treated lesion 4 (23.5%) achieved confirmed partial responses. 10 of 12 pts with quantifiable HCV experienced a marked reduction in viral load. 6-week tumor biopsies showed clear increase in CD8+ T cells only in pts showing a clinical response. Flow cytometry of PBMC revealed statistically significant changes in CD4/Treg and CD8/Treg ratio only in patients showing clinical response. Median PFS for evaluable HCC population was 5.7m. Conclusions: Tremelimumab in combination with subtotal TACE, RFA or CA in patients with advanced HCC and BTC is safe and leads to the accumulation of intratumoral CD8+ T cells, activation of CD4+ and CD8+ T cells in peripheral blood in responding patients. Encouraging clinical activity seen with objective confirmed responses, PFS 5.7m and possibly surrogate reductions in HCV viral load. Clinical trial information: NCT01853618