Autologous Dendritic Cell Vaccine for Treatment of Patients With Chronic HCV-Infection
Condition: Hepatitis C, Chronic; Liver Diseases; Hepatitis; Virus Diseases
MeSH terms: Infections; Hepatitis A; Hepatitis C; Virus Diseases; Hepatitis C, Chronic; Hepatitis; Liver Diseases
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Clearance of HCV infection requires early and multi-specific HLA class I restricted CD8+ T
      cell and class II restricted CD4+ T cell responses to both structural (Core) and
      non-structural HCV proteins (NS3, NS4A, NS5A, NS5B). Dendritic cells (DCs) are professional
      antigen-presenting cells that link innate and adaptive immune responses, and play a major
      role in priming, initiating, and sustaining strong anti-HCV T cell immune responses.

      The general objective of this study is to evaluate safety, feasibility and clinical efficacy
      of therapeutic vaccination in genotype 1 HCV patients using autologous DCs pulsed with
      recombinant HCV-antigens (Core and NS3). Expected effects: DC vaccination induces
      Core/NS3-specific immune response and reduces viral load in patients with chronic
      HCV-infection.
    

Detailed description: 
      Hepatitis C virus (HCV) has chronically infected an estimated 170 million people worldwide.
      People infected with HCV are at risk for developing chronic liver diseases, such as liver
      cirrhosis and primary hepatocellular carcinoma. It has been estimated that HCV accounts for
      27% of cirrhosis and 25% of hepatocellular carcinoma worldwide. Therapy for chronically
      HCV-infected patients has involved a pegylated interferon-alpha and ribavirin (pegIFN/RBV)
      and is still the only FDA-approved therapeutic combination. However, this therapy is
      expensive, non-specific, toxic, and only effective in about 50% of genotype-1 HCV patients.

      An early immune response, represented by the activation of NK cells, the development of
      vigorous anti-HCV CD4+ and CD8+ T-cell responses, and the appearance of HCV-specific
      antibodies, is mounted by the host during acute HCV infection and leads to clearance of the
      virus. However, in the vast majority (≈85%) of infected individuals HCV causes a persistent
      infection. The mechanisms of HCV persistence remain elusive and are largely related to
      inefficient clearance of the virus by the host immune system.

      Although HCV genome is very variable with hundreds of serotypes and six genotypes, several
      structural (Core) and nonstructural proteins (NS3, NS4A, NS5A, NS5B) are highly conserved
      among genotypes and subtypes. It is apparent that clearance of hepatitis C infection requires
      early and multi-specific HLA class I restricted CD8+ T cell and class II restricted CD4+ T
      cell responses to both structural and non-structural HCV proteins.

      DCs are professional antigen-presenting cells that link innate and adaptive immune responses.
      DCs play a major role in priming, initiating, and sustaining strong T cell responses against
      pathogen-derived antigens. Therefore DC-based therapy represents a promising
      immunotherapeutic approach in terms of their propensity to establish anti-HCV adaptive immune
      responses.

      This trial is a prospective, non-blinded, interventional study to determine safety,
      feasibility and clinical efficacy of therapeutic vaccination in genotype 1 HCV patients using
      autologous DCs pulsed with recombinant HCV-antigens (Core and NS3). Our previous work has
      shown that the short-term loading of DCs with recombinant HCV proteins Core (1-120) and NS3
      (1192-1457) have no any marked inhibitory effect on maturation and functions of DCs.

      In experimental group thirty patients with chronic hepatitis C (genotype 1) will be
      vaccinated via intracutaneous injection of monocyte-derived DCs, generated in the presence of
      IFN-α/GM-CSF and pulsed with recombinant HCV Core (1-120) and NS3 (1192-1457) proteins. The
      vaccination protocol will includes initiating (one injection per week, no 4) and maintaining
      (one injection per month, no 6) courses with subsequent 6-month of follow up.

      The safety will be determined by the evaluation of the number of participants with the
      adverse events. Liver safety will be assessed by blood analysis and Ultrasound. Patients will
      be monitored in a 2 months (after completing of initiating course), 7 months (after
      completing of maintaining course) and 13 months (in a 6 months post-vaccination follow-up).
    

Intervention name(s): Autologous DC-vaccines
Intervention type(s): Biological
Intervention description(s): Patients will be vaccinated via intracutaneous injection of autologous DCs (5×106) combined with adjuvant subcutaneous injection of recombinant hIL-2 (250 000 IU).
Initiating course: one vaccination per week, during 1 month. Maintaining course: one vaccination per month, during 6 month. Patients will be monitored in a 2 months (after completing of initiating course), 7 months (after completing of maintaining course) and 13 months (in a 6 months post-vaccination follow-up).
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Dendritic Cells; DC-based Vaccines; Chronic HCV Infection; Antigen-Specific T cell response; Recombinant HCV-Core antigen; Recombinant HCV-NS3 antigen