Hepatocellular carcinoma (HCC) occurs most commonly secondary to cirrhosis due to chronic hepatitis C or B virus (HCV/HBV) infections. Type I interferon (IFN-α) treatment of chronic HCV/HBV infections reduces the incidence of HCC in cirrhotic patients. However, IFN-α toxicity limits its tolerability and efficacy highlighting a need for better therapeutic treatments. A recently discovered type III IFN (IFN-λ) has been shown to possess antiviral properties against HCV and HBV in vitro. In phase I clinical trials, IFN-λ treatment did not cause significant adverse reactions. Using a gene therapy approach, we compared the antitumor properties of IFN-α and IFN-λ in a transplantable hepatoma model of HCC. BALB/c mice were inoculated with syngeneic BNL hepatoma cells, or BNL cells expressing IFN-λ (BNL.IFN-λ cells) or IFN-α (BNL.IFN-α cells). Despite the lack of antiproliferative activity of IFNs on BNL cells, both BNL.IFN-λ and BNL.IFN-α cells displayed retarded growth kinetics in vivo. Depletion of NK cells from splenocytes inhibited splenocyte-mediated cytotoxicity, demonstrating that NK cells play a role in IFN-induced antitumor responses. However, isolated NK cells did not respond directly to IFN-λ. There was also a marked NK cell infiltration in IFN-λ producing tumors. In addition, IFN-λ and, to a lesser extent, IFN-α enhanced immunocytotoxicity of splenocytes primed with irradiated BNL cells. Splenocyte cytotoxicity against BNL cells was dependent on IL-12 and IFN-λ, and mediated by dendritic cells. In contrast to NK cells, isolated from spleen CD1 1c+ and mPDCA+ dendritic cells responded directly to IFN-λ. The antitumor activities of IFN-λ against hepatoma, in combination with HCV and HBV antiviral activities warrant further investigation into the clinical use of IFN-λ to prevent HCC in HCV/HBV-infected cirrhotic patients, as well as to treat liver cancer.

Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer. No significant improvement has been reported with currently available systemic therapies. IFN-α has been tested in both clinic and animal models and only moderate benefits have been observed. In animal models, similar modest antitumor efficacy has also been reported for IFN-λ, a new type of IFN that acts through its own receptor complex. In the present study, the antitumor efficacy of the combination of IFN-α and IFN-λ was tested in the BNL mouse hepatoma model. This study was accomplished by using either engineered tumor cells (IFN-α/IFN-λ gene therapy) or by directly injecting tumor-bearing mice with IFN-α/IFN-λ. Both approaches demonstrated that IFN-α/IFN-λ combination therapy was more efficacious than IFN monotherapy based on either IFN-α or IFN-λ. In complement to tumor surgery, IFN-α/IFN-λ combination induced complete tumor remission. Highest antitumor efficacy has been obtained following local administration of IFN-α/IFN-λ combination at the tumor site that was associated with strong NK cells tumor infiltration. This supports the use of IFN-α/IFN-λ combination as a new cancer immunotherapy for stimulating antitumor response after cancer surgery.

PurposeTo determine the safety of an approach to immunologically enhance local treatment of hepatocellular cancer (HCC) by combining nonlethal radiation, local regional therapy with intratumoral injection, and systemic administration of a potent Toll-like receptor (TLR) immune adjuvant.MethodsPatients with HCC not eligible for liver transplant or surgery were subject to: 1) 3 fractions of 2-Gy focal nonlethal radiation to increase tumor antigen expression, 2) intra-/peri-tumoral (IT) injection of the TLR3 agonist, polyinosinic-polycytidylic acid polylysine carboxymethylcellulose (poly-ICLC), to induce an immunologic “danger” response in the tumor microenvironment with local regional therapy, and 3) systemic boosting of immunity with intramuscular poly-ICLC. Primary end points were safety and tolerability; secondary end points were progression-free survival (PFS) and overall survival (OS) at 6 months, 1 year, and 2 years.ResultsEighteen patients with HCC not eligible for surgery or liver transplant were treated. Aside from 1 embolization-related severe adverse event, all events were ≤grade II. PFS was 66% at 6 months, 39% at 12 months, and 28% at 24 months. Overall 1-year survival was 69%, and 2-year survival 38%. In patients <60 years old, 2-year survival was 62.5% vs. 11.1% in patients aged >60 years (P<0.05). Several patients had prolonged PFS and OS.ConclusionIntra-tumoral injection of the TLR3 agonist poly-ICLC in patients with HCC is safe and tolerable when combined with local nonlethal radiation and local regional treatment. Further work is in progress to evaluate if this approach improves survival compared to local regional treatment alone and characterize changes in anticancer immunity.

Intravenous drug use and sexual practices account for 60% of hepatitis C (HCV) and B (HBV) infection. Disclosing these activities can be embarrassing and reduce risk reporting, blood testing and diagnosis. In diagnosed patients, linkage to care remains a challenge. Audio-computer-assisted survey interview (Audio-CASI) was used to guide HCV and HBV infection testing in urban clinics. Risk reporting, blood testing and serology results were compared to historical controls. A patient navigator (PN) followed up blood test results and provided patients with positive serology linkage to care (LTC). Of 1932 patients surveyed, 574 (30%) were at risk for chronic viral hepatitis. A total of 254 (44.3%) patients were tested, 34 (13.5%) had serology warranting treatment evaluation, and 64% required HBV vaccination. Of 16 patients with infection, seven HCV and three HBV patients started treatment following patient LTC. Of 146 HBV-naïve patients, 70 completed vaccination. About 75% and 49% of HCV antibody and HBV surface antigen-positive patients were born between 1945 and 1965. Subsequently, automated HCV testing of patients born between 1945 and 1965 was built into our hospital electronic medical records. Average monthly HCV antibody testing increased from 245 (January-June) to 1187 (July-October). Patient navigator directed LTC for HCV antibody-positive patients was 61.6%. In conclusion, audio-CASI can identify patients at risk for HCV or HBV infection and those in need of HBV vaccination in urban medical clinics. Although blood testing once a patient is identified at risk for infection needs to increase, a PN is useful to provide LTC of newly diagnosed patients.

390 Background: Propranolol and etodolac (designated VT-122) target the adrenergic and prostaglandin stress systems activated in HCC. These stress-induced systems are proposed to induce changes in the tumor microenvironment and immune system leading to tumor promotion and immune tolerance. In a separate study, administration of VT-122 prior to sorafenib showed an increase in median overall survival (OS) of 21 months when VT-122 is administered before sorafenib compared to 10 months OS for sorafenib alone. The aim of the current study was to evaluate the effect of administering VT-122 at least 30 days after starting sorafenib. Methods: Patients with HCC receiving sorafenib for at least 30 days were eligible for this double-blind, placebo-controlled study. Patients were randomized to receive sorafenib with either VT-122 or placebo. Patients received therapy for up to 12 months or until treatment failure. VT-122 was administered twice daily. The primary endpoint was duration of therapy (DoT) and the secondary endpoint was OS. Results: Twenty patients were randomized, 11 and 9 patients to the VT122 and placebo arm, respectively. Each arm was balanced with regards to age (mean of 60.4 years), Child Pugh status (9 Child Pugh A, 11 Child Pugh B7), hepatitis virus status (6 HBV and 1 HCV positive) and C-reactive protein (CRP) (20.4 mg/L). VT122 with sorafenib was well tolerated with no unexpected serious adverse events reported. Mean OS was 13.9 months and 9.6 months in the VT-122 and placebo arms, respectively. Mean DoT (unvalidated) was 10.1 months and 7.5 months in the VT-122 and placebo arms, respectively. Conclusions: Co-administration of VT-122 with sorafenib was well tolerated and showed an increase in duration of therapy and OS versus sorafenib alone. The small sample size and number of events precludes the ability to make any significant efficacy conclusions. The increase in survival was not as great as that seen in a separate study in which VT122 was started prior to sorafenib. A further Phase 3 study of VT122 administered prior to sorafenib in patients with HCC is warranted. Clinical trial information: NCT01265576.