Clinical trial NCT03119025: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Hepatitis C, Chronic
Liver Diseases
Hepatitis
Virus Diseases
Keywords: Dendritic Cells
DC-based Vaccines
Chronic HCV Infection
Antigen-Specific T cell response
Recombinant HCV-Core antigen
Recombinant HCV-NS3 antigen
Lead sponsor: Russian Academy of Medical Sciences
Sponsor class: OTHER
First posted: 2017-04-18
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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

Primary outcomes:
measure: Number of Participants With Severe Adverse Reactions and/or With Abnormal Clinical Laboratory Values That Are Related to Treatment
timeFrame: From enrollment and up to 13 months
Secondary outcomes:
measure: Number of Participants With Virological Response According to HCV RNA Viral Load
timeFrame: Baseline, 2, 7 and 13 months after 1-st vaccination
measure: Number of Participants Who Have Developed or Increased Anti-Viral Immune Response According to T-cell Proliferation
timeFrame: Baseline, 2, 7, and 13 months after 1-st vaccination
measure: Number of Participants Who Have Developed or Increased Anti-Viral Immune Response According to IFN-γ Production
timeFrame: Baseline, 2, 7 and 13 months after 1-st vaccination
Other outcomes:
Locations:
city: Novosibirsk
country: Russian Federation
facility: Institute of Fundamental and Clinical Immunology
Study officials:
affiliation: Institute of Fundamental and Clinical Immunology
name: Elena R Chernykh, MD, PhD
role: STUDY_CHAIR
affiliation: Institute of Fundamental and Clinical Immunology
name: Alexander A Ostanin, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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