Hepatitis, Hepatitis C, Chronic, Liver Diseases, Virus Diseases
Conditions
Keywords
Dendritic Cells, DC-based Vaccines, Chronic HCV Infection, Antigen-Specific T cell response, Recombinant HCV-Core antigen, Recombinant HCV-NS3 antigen
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).
Interventions
BIOLOGICALAutologous 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).
Sponsors
Russian Academy of Medical Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Severe Adverse Reactions and/or With Abnormal Clinical Laboratory Values That Are Related to Treatment | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Virological Response According to HCV RNA Viral Load | Baseline, 2, 7 and 13 months 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) |
| Number of Participants Who Have Developed or Increased Anti-Viral Immune Response According to T-cell Proliferation | 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 |
| Number of Participants Who Have Developed or Increased Anti-Viral Immune Response According to IFN-γ Production | 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 |
Countries
Russia
Participant flow
Recruitment details
The recruitment, assessment and treatment of patients were conducted from May 2015 to November 2016 in a Clinic of Immunopathology affiliated with Institute of Fundamental and Clinical Immunology, that currently holds a license for cell technology application.
Participants by arm
| Arm | Count |
|---|---|
| Autologous DC-vaccines Ten patients with chronic hepatitis C (genotype 1) were received the initiating and maintaining courses of autologous monocyte-derived dendritic cells, generated in the presence of IFN-α/GM-CSF and loaded with recombinant HCV Core (1-120) and NS3 (1192-1457) proteins.
Autologous DC-vaccines: Patients were 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 were monitored at baseline (before the first vaccination) and 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). | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Autologous DC-vaccines |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 35.5 years |
| Patients with chronic hepatitis C (genotype 1b) | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment Russia | 10 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 10 |
| other Total, other adverse events | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
Primary
Number of Participants With Severe Adverse Reactions and/or With Abnormal Clinical Laboratory Values That Are Related to Treatment
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).
Time frame: From enrollment and up to 13 months
Population: Most patients had minimal hepatitis activity as evidenced by normal or slightly increased liver transaminase levels. Serum HCV RNA levels ranged from 1.3 × 104 IU/mL to 1.8 × 106 IU/mL. Fibrosis stage ranged from F0 to F3 according to Metavir system scores.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Autologous DC-vaccines | Number of Participants With Severe Adverse Reactions and/or With Abnormal Clinical Laboratory Values That Are Related to Treatment | 0 Participants |
Secondary
Number of Participants Who Have Developed or Increased Anti-Viral Immune Response According to IFN-γ Production
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
Time frame: Baseline, 2, 7 and 13 months after 1-st vaccination
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Autologous DC-vaccines | Number of Participants Who Have Developed or Increased Anti-Viral Immune Response According to IFN-γ Production | 9 Participants |
Secondary
Number of Participants Who Have Developed or Increased Anti-Viral Immune Response According to T-cell Proliferation
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
Time frame: Baseline, 2, 7, and 13 months after 1-st vaccination
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Autologous DC-vaccines | Number of Participants Who Have Developed or Increased Anti-Viral Immune Response According to T-cell Proliferation | 9 Participants |
Secondary
Number of Participants With Virological Response According to HCV RNA Viral Load
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)
Time frame: Baseline, 2, 7 and 13 months after 1-st vaccination
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Autologous DC-vaccines | Number of Participants With Virological Response According to HCV RNA Viral Load | 4 Participants |