Background & Aims Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of activated T lymphocytes. Ablative therapies induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced hepatocellular carcinoma (HCC). This study aimed to demonstrate whether tremelimumab could be combined safely and feasibly with ablation. Methods Thirty-two patients with HCC were enrolled: male:female: 28:4; median age: 62 (range 36–76). Patients were given tremelimumab at two dose levels (3.5 and 10 mg/kg i.v.) every 4 weeks for 6 doses, followed by 3-monthly infusions until off-treatment criteria were met. On day 36, patients underwent subtotal radiofrequency ablation or chemoablation. Staging was performed by contrast-enhanced CT or MRI scan every 8 weeks. Results No dose-limiting toxicities were encountered. The most common toxicity was pruritus. Of the 19 evaluable patients, five (26.3%; 95% CI: 9.1–51.2%) achieved a confirmed partial response. Twelve of 14 patients with quantifiable HCV experienced a marked reduction in viral load. Six-week tumor biopsies showed a clear increase in CD8+ T cells in patients showing a clinical benefit only. Six and 12-month probabilities of tumor progression free survival for this refractory HCC population were 57.1% and 33.1% respectively, with median time to tumor progression of 7.4 months (95% CI 4.7 to 19.4 months). Median overall survival was 12.3 months (95% CI 9.3 to 15.4 months). Conclusions Tremelimumab in combination with tumor ablation is a potential new treatment for patients with advanced HCC, and leads to the accumulation of intratumoral CD8+ T cells. Positive clinical activity was seen, with a possible surrogate reduction in HCV viral load. Lay summary Studies have shown that the killing of tumors by direct methods (known as ablation) can result in the immune system being activated or switched on. The immune system could potentially also recognize and kill the cancer that is left behind. There are new drugs available known as immune checkpoint inhibitors which could enhance this effect. Here, we test one of these drugs (tremelimumab) together with ablation.

Objectives Hepatocellular carcinoma (HCC) incidence has been increasing in the United States for several decades. As the incidence of hepatitis C virus (HCV) infection declines and the prevalence of metabolic disorders rises, the proportion of HCC attributable to various risk factors may be changing. Methods Data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linkage were used to calculate population attributable fractions (PAFs) for each risk factor over time. HCC cases (n=10,708) diagnosed during the years 2000–2011 were compared to a 5% random sample of cancer-free persons (n=332,107) residing in the SEER areas. Adjusted odds ratios (ORs) and PAFs were calculated for hepatitis C virus (HCV), hepatitis B virus (HBV), metabolic disorders, alcohol-related disorders, smoking, and genetic disorders. Results Overall, the PAF was greatest for metabolic disorders (32.0%), followed by HCV (20.5%), alcohol (13.4%), smoking (9.0%), HBV (4.3%) and genetic disorders (1.5%). The PAF for all factors combined was 59.5%. PAFs differed by race/ethnicity and gender. Metabolic disorders had the largest PAF among Hispanics (39.3%, CI=31.9–46.7%) and whites (34.8%, CI=33.1–36.5%), while HCV had the largest PAF among blacks (36.1%, CI=31.8–40.4%) and Asians (29.7%, CI=25.9–33.4%). Between 2000 and 2011, the PAF of metabolic disorders increased from 25.8% (CI=22.8–28.9%) to 36.0% (CI=33.6–38.5%). In contrast, the PAFs of alcohol-related disorders and HCV remained stable. Conclusions Among U.S. Medicare recipients, metabolic disorders contribute more to the burden of HCC than any other risk factor and the fraction of HCC due to metabolic disorders has increased in the last decade.