A phase I clinical trial of dendritic cell immunotherapy in HCV-infected individuals

Abstract

Background & Aims HCV patients who fail conventional interferon-based therapy have limited treatment options. Dendritic cells are central to the priming and development of antigen-specific CD4+ and CD8+ T cell immunity, necessary to elicit effective viral clearance. The aim of the study was to investigate the safety and efficacy of vaccination with autologous dendritic cells loaded with HCV-specific cytotoxic T cell epitopes. Methods We examined the potential of autologous monocyte derived dendritic cells (MoDC), presenting HCV-specific HLA A2.1-restricted cytotoxic T cell epitopes, to influence the course of infection in six patients who failed conventional therapy. Dendritic cells were loaded and activated ex vivo with lipopeptides. In this phase 1 dose escalation study, all patients received a standard dose of cells by the intradermal route while sequential patients received an increased dose by the intravenous route. Results No patient showed a severe adverse reaction although all experienced transient minor side effects. HCV-specific CD8+ T cell responses were enumerated in PBMC by ELIspot for interferon-γ. Patients generated de novo responses, not only to peptides presented by the cellular vaccine but also to additional viral epitopes not represented in the lipopeptides, suggestive of epitope spreading. Despite this, no increases in ALT levels were observed. However, the responses were not sustained and failed to influence the viral load, the anti-HCV core antibody response and the level of circulating cytokines. Conclusions Immunotherapy using autologous MoDC pulsed with lipopeptides was safe, but was unable to generate sustained responses or alter the outcome of the infection. Alternative dosing regimens or vaccination routes may need to be considered to achieve therapeutic benefit.

High, Broad, Polyfunctional, and Durable T Cell Immune Responses Induced in Mice by a Novel Hepatitis C Virus (HCV) Vaccine Candidate (MVA-HCV) Based on Modified Vaccinia Virus Ankara Expressing the Nearly Full-Length HCV Genome

“…This is the first time in which all of the HCV proteins are expressed in the same context by a single virus vector. Usually, the HCV vaccine candidates target the structural proteins (Core, E1, and E2) (42)(43)(44)(45), a combination of structural and nonstructural proteins (Core, NS3, and NS4) (46)(47)(48), or the nonstructural proteins (generally NS3, NS4, and NS5) (20,25). Undoubtedly, the most frequently used HCV antigen is NS3 since the majority of the viral epitopes recognized by cytotoxic T lymphocytes and CD4 ϩ T cells in patients with HCV infection are located in this protein (9,49).…”

Mobilizing monocytes to cross-present circulating viral antigen in chronic infection

“…This strategy may be extended to other persistent infections and potentially open new avenues for immunotherapy. Currently, in vitrocultured moDCs loaded with recombinant antigens have been used to vaccinate patients with chronic HBV (47,48), HCV (49), and HIV (50-52) infection. These vaccines can enhance virus-specific T cell responses, but are hindered by the need to select appropriate antigens and a GMP cell production facility to produce the vaccine.…”

Dendritic cells in hepatitis C infection: can they (help) win the battle?

“…The most advanced translational investigation to date was performed by Gowans et al [155], in which the researchers took the DC-based approach one step forward and performed a phase I clinical trial of self-derived DC immunotherapy in HCV-infected individuals who had failed conventional therapy. In this study the authors evaluated the use of lipopeptide vaccine candidates containing HLA-A2-restricted epitopes for DC-based immunotherapy of HCV infection.…”