CHICAGO—Treatment with tremelimumab stabilized patients with advanced hepatocellular carcinoma due to chronic hepatitis C infection for more than 12 months, according to data from a phase II clinical trial presented by lead researcher Ignacio Melero, MD, PhD, consultant in the department of oncology and professor and senior investigator in El Centro de Investigacion Medica Aplicada at the Universidad de Navarra, Pamplona, Spain (AACR abstract 4387).
The researchers evaluated 21 patients treated with tremelimumab intravenously at a dose of 15 mg/kg every 90 days for about two cycles. Tumor burden was reduced for 2 patients, and disease stabilized for more than a year in 11 patients.
Tremelimumab is a fully human monoclonal antibody that binds to CTLA-4 expressed on the surface of activated T lymphocytes, resulting in inhibition of B7-CTLA-4-mediated down-regulation of T-cell activation.
“The unique conditions [of hepatocellular carcinoma and hepatitis C infection] permitted us to monitor the antitumor effects and immune response to well-defined viral antigens, killing two birds with one stone,” said Dr. Melero.
In an intention-to-treat analysis, investigators observed a median overall survival of 7.5 months and time to progression of 6.4 months. They reported treatment-related adverse events among 80% of patients. Grade 3 or higher adverse events included 1 case of pruritus, 1 case of purpura, and 5 cases of elevated transaminases.
Dr. Melero and colleagues also observed a reduction of hepatitis C virus (HCV) in the patients’ blood, which was also accompanied with objective enhancements of antiviral immunity. A significant and progressive decline in serum HCV viral load was observed (median values: baseline 3.78x10e5 copies/ml vs day 120 3.02x10e4 copies/ml, P = .02; vs day 210 1.69x10e3 copies/ml, P = .04). “This was associated with an increase in anti-HCV immune response in 76% of patients,” said Dr. Melero. (Response was evaluated by measuring at different time points IFN-g spot forming cells after incubation of PBMC with pools of peptides spanning the whole HCV polyprotein and recombinant core, NS3, NS4, and NS5 proteins.) A significant increase in circulating CD4+Foxp3+ cells was also observed at day 30.
“The short series of patients already showing clinical activity offers clear signs for the need to extend these trials,” said Dr. Melero. “It is unusual to spot clear signs of clinical activity with such a small number of patients, and the information on antiviral activity is also very promising.”
Commenting on the findings, Dr. Shivakumar Chitturi of the Australian National University Medical School, said, “The drug looks promising but all the usual caveats apply: small numbers, modest improvement in survival, etc.” Despite these words of caution, Dr. Chitturi observed, “The effects on the immune system are interesting because this throws up a new line of attack.”
The study was supported by Pfizer. Tremelimumab has been licensed by MedImmune to develop and commercialize the drug for treatment of cancer.