Safety/Efficacy of Vaccination With Autologous Dendritic Cells Pulsed With Recombinant HCV-Antigens (Core and NS3) for Treatment of Patients With Chronic HCV-Infection
Phase: PHASE1
Conditions: Hepatitis C, Chronic, Liver Diseases, Hepatitis, Virus Diseases
Sponsor: Russian Academy of Medical Sciences

Study Identification 
 
Unique Protocol ID: IFCI-04/10/2015 
Brief Title: Autologous Dendritic Cell Vaccine for Treatment of Patients with Chronic HCV-
Infection  
Official Title: Safety/Efficacy of Vaccination with Autologous Dendritic Cells Pulsed with 
Recombinant HCV-Antigens (Core and NS3) for Treatment of Patients with Chronic HCV-
Infection 
 
The protocol was approved by the Ethics Committee of the Institute of Fundamental and Clinical 
Immunology (approval number: no 88, 04/10/2015) 
 
Study Description 
 
Purpose/Brief Summary: 
 
Clearance of HCV infection requires earlyand 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 vaccinationin 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. 
 
Condition 
Intervention 
Phase 
Hepatitis C, Chronic 
Biological: Autologous monocyte-derived dendritic cells, 
generated in the presence of IFN-α/GM-CSF and pulsed 
with recombinant HCV Core (1-120) and NS3 (1192-1457) 
proteins. 
Phase 1 
Phase  2 
 
 
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. 

2 
 
 
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 [Oleynik 
E.A., et al. 2016]. 
 
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). 
 
Conditions 
Conditions: Hepatitis C, Chronic; Liver Diseases; Hepatitis, Viral, Human; Hepatitis, Chronic; 
Virus Diseases. 
 
Keywords: Dendritic Cells; DC-based Vaccines; Chronic HCV Infection; Antigen-Specific T 
cell response; Recombinant HCV-Core antigen; Recombinant HCV-NS3 antigen. 
 
Study Design 
Study Type: Interventional 
Primary Purpose: Treatment 
Study Phase: Phase 1/Phase 2 
Intervention Model: Single Group Assignment 
Number of Arms: 1 
Masking: No masking 
Enrollment: 30  
 
Arms and Interventions 
Arms 
Assigned Interventions 
Experimental:  Autologous  DC-vaccines  
 
Thirty patients with chronic hepatitis C 
(genotype 1) will receive the initiating and 
maintaining courses of autologous  
monocyte-derived dendritic cells, 
generated in the presence of IFN-α/GM-
CSF and pulsed with recombinant HCV 
Core (1-120) and NS3 (1192-1457) 
proteins. 
Biological/Vaccine:    Autologous DC-vaccines 
 
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 

3 
 
 
Outcome Measures 
Primary Outcome Measure: 
 
1. Number of Participants with Severe Adverse Reactions and/or With Abnormal Clinical 
Laboratory Values That Are Related to Treatment  
[Time Frame: From enrollment and up to 13 months]  
Frequency of severe adverse reactions will be evaluated from enrollment and up to 13 months. 
Liver safety by blood analysis (ALT, AST, GGT, Total and conjugated bilirubin, platelets, ESR, 
etc) and Ultrasound will be assessed from enrollment and up to 13 months (= baseline, 2, 7 and 
13 months after 1-st vaccination). 
 
Secondary Outcome Measure: 
 
2. Number of Participants with Virological Response According to HCV RNA Viral Load 
[Time Frame: Baseline, 2, 7 and 13 month after 1-st vaccination]  
Virological response in patients receiving DC-vaccinations is defined as change from baseline in 
HCV RNA viral load by at least 1 log at 2, 7 and 13 month after 1-st vaccination. Plasma level of 
HCV RNA will be measured by Real-Time Reverse Transcription-Polymerase Chain Reaction 
(RT-PCR) 
 
3. Number of Participants Who Have Developed or Increased Anti-Viral Immune Response 
According to T-cell proliferation 
[Time Frame: Baseline, 2, 7, and 13 months after 1-st vaccination]  
Change from baseline in T-cell proliferative response to HCV Core and NS3 proteins at 2, 7 and 
13 month after 1-st vaccination. T-cell proliferation will be evaluated using radiometry based on 
3H-thymidine incorporation. 
 
4. Number of Participants Who Have Developed or Increased Anti-Viral Immune Response 
According to IFN-γ production 
[Time Frame: Baseline, 2, 7, and 13 months after 1-st vaccination]  
Change from baseline in T-cell IFN-γ-producing response to HCV Core and NS3 proteins at 2, 7 
and 13 month after 1-st vaccination. Production of IFN-γ will be measured by ELISA kit 
 
 
Eligibility 
 
Minimum Age: 18 Years 
Maximum Age: 65 Years 
Sex: All 
Accepts Healthy Volunteers: No 
 
Criteria:  
Inclusion Criteria: 
 Age 18 to 65 Years (Adult) 
 Chronic hepatitis C (genotype 1b) 
 HCV-positive patients  
 Plasma HCV RNA level ≥ 104 IU/ml 
 Liver fibrosis (METAVIR Score 0-III) 
completing of maintaining course) and 13 months 
(in a 6 months post-vaccination follow-up). 

4 
 
 Patients must be able totolerate all study procedures 
 Patients must be willing to voluntarily give written Informed Consent to participate in the 
study before any procedures are performed 
 Patients must be willing to be available for all baseline, treatment and follow-up 
examinations required by protocol  
 
Exclusion Criteria: 
 Co-infection with hepatitis B, A, D, E, cytomegalovirus or Epstein-Barr virus 
 Liver cirrhosis (METAVIR Score IV) 
 The high degree of hepatitis activity (ALT and/or AST ≥ 10 ULN) 
 Received any vaccine within a month prior to study entry  
 A history of diabetes 
 Psychiatric disorders 
 Renal dysfunctions 
 Hemodynamic or respiratory instability 
 HIV or uncontrolled bacterial, fungal, or viral infections 
 Autoimmune diseases  
 Pregnancy 
 Malignancy 
 Participation in other clinical trials 
 
Contacts/Locations 
Central Contact: Natalia M Starostina, PhD 
 
Telephone: +7 (383) 228-27-41 
Email: starostina48@bk.ru 
 
Central Contact Backup: OlgaYLeplina 
Telephone: +7 (383) 228-21-01 
Email: oleplina@mail.ru 
 
Study Chair: Elena R Chernykh, MD, PhD 
 
Study Principal Investigator: Alexander A Ostanin, MD, PhD 
 
Locations: Institute of Fundamental and Clinical Immunology 
Novosibirsk, Russian Federation, 630099 
 
 
References 
 
Oleynik E.A., Leplina O.Y., Tyrinova T.V., Tikhonova M.A., Pyrinova G.B., Ostanin A.A., 
Starostina N.M., Chernykh E.R. The influence of recombinant HCV proteins Core and NS3 on 
maturation and functions of dendritic cells generated in vitro with interferon-alpha. Immunology 
37 (5): 239-245, 2016. (in Russian) DOI: 10.18821/0206-4952-2016-37-5-239-245