title: A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C.
abstract: OBJECTIVE
  Tremelimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), an inhibitory co-receptor that interferes with T cell activation and proliferation. The purpose of this pilot clinical trial was to test the antitumor and antiviral effect of tremelimumab in patients with hepatocellular carcinoma (HCC) and chronic hepatitis C virus (HCV) infection; and to study the safety of its administration to cirrhotic patients.
  
  
  METHODS
  Tremelimumab at a dose of 15 mg/kg IV every 90 days was administered until tumor progression or severe toxicity. Twenty patients were assessable for toxicity and viral response and 17 were assessable for tumor response. Most patients were in the advanced stage and 43% had an altered liver function (Child-Pugh class B).
  
  
  RESULTS
  A good safety profile was recorded and no patient needed steroids because of severe immune-mediated adverse events. Some patients had a transient albeit intense elevation of transaminases after the first dose, but not following subsequent cycles. Partial response rate was 17.6% and disease control rate was 76.4%. Time to progression was 6.48 months (95% CI 3.95-9.14). A significant drop in viral load was observed while new emerging variants of the hypervariable region 1 of HCV replaced the predominant variants present before therapy, particularly in those patients with a more prominent drop in viral load. This antiviral effect was associated with an enhanced specific anti-HCV immune response.
  
  
  CONCLUSIONS
  Tremelimumab safety profile and antitumor and antiviral activity, in patients with advanced HCC developed on HCV-induced liver cirrhosis, support further investigation.
authors: Liver Unit and HPB Oncology, Clinica Universidad de Navarra, Pamplona, Spain. bsangro@unav.es
authors: Bruno
authors: B
authors: Sangro
authors: Carlos
authors: C
authors: Gomez-Martin
authors: Manuel
authors: M
authors: de la Mata
authors: Mercedes
authors: M
authors: Iñarrairaegui
authors: Elena
authors: E
authors: Garralda
authors: Pilar
authors: P
authors: Barrera
authors: Jose Ignacio
authors: JI
authors: Riezu-Boj
authors: Esther
authors: E
authors: Larrea
authors: Carlos
authors: C
authors: Alfaro
authors: Pablo
authors: P
authors: Sarobe
authors: Juan José
authors: JJ
authors: Lasarte
authors: Jose L
authors: JL
authors: Pérez-Gracia
authors: Ignacio
authors: I
authors: Melero
authors: Jesús
authors: J
authors: Prieto
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D006528:Carcinoma, Hepatocellular / Q000150:complications* / Q000276:immunology / Q000628:therapy*; D005260:Female; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000150:complications* / Q000628:therapy* / Q000821:virology; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications / Q000276:immunology / Q000628:therapy; D008113:Liver Neoplasms / Q000150:complications* / Q000276:immunology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D019562:Viral Load
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D060908:CTLA-4 Antigen; C520704:tremelimumab