Autologous Dendritic Cell Vaccine for Treatment of Patients With Chronic HCV-Infection

NCT ID: NCT03119025

Last Updated: 2019-05-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-05-31
• Study Completion Date: 2018-04-30

Brief 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).

Conditions

Hepatitis C, Chronic; Liver Diseases; Hepatitis; Virus Diseases

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Autologous DC-vaccines

Thirty patients with chronic hepatitis C (genotype 1) will receive the initiating and maintaining courses of autologous 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.

Group Type: EXPERIMENTAL

Autologous DC-vaccines

Intervention Type: BIOLOGICAL

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).

Interventions

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 completing of maintaining course) and 13 months (in a 6 months post-vaccination follow-up).

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

• Age 18 to 65 Years (Adult)
• Chronic hepatitis C (genotype 1b)
• HCV-positive patients
• Plasma HCV RNA level ≥ 10 000 IU/ml
• Liver fibrosis (METAVIR Score 0-III)
• Patients must be able to tolerate 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Russian Academy of Medical Sciences

OTHER

Sponsor Role: lead

Responsible Party

Alexander A Ostanin

Head of Clinical Department

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Elena R Chernykh, MD, PhD

Role: STUDY_CHAIR

Institute of Fundamental and Clinical Immunology

Alexander A Ostanin, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Institute of Fundamental and Clinical Immunology

Locations

Institute of Fundamental and Clinical Immunology

Novosibirsk, , Russia

Countries

Russia

References

Oleynik EA, Leplina OY, Tyrinova TV, Tikhonova MA, Pyrinova GB, Ostanin AA, Starostina NM, Chernykh ER. 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

Reference Type: BACKGROUND

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Study Documents

Document Type: Clinical Study Report

Chernykh E., Leplina O., Oleynik E., Tikhonova M., Tyrinova T., Starostina N., Ostanin A. Immunotherapy with interferon-α-induced dendritic cells for chronic HCV infection (the results of pilot clinical trial) // Immunologic Research.- 2017

View Document

Other Identifiers

IFCI-04/10/2015

Identifier Type: -

Identifier Source: org_study_id