Dendritic Cell Vaccine in HIV-1 Infection

Study Overview
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Brief Summary
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To study the efficacy of a therapeutic HIV vaccine consisting of autologous myeloid dendritic cells pulsed ex vivo with high doses of inactivated autologous HIV-1, in HIV-1 infected patients in a very early stages of the disease (CD4 > 450 x 10 6 /L). To analyze the HIV-1 humoral and cellular immune responses induced by this immune-based therapy.

Detailed Description
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Our group has reported recently the first human trial of 4 therapeutic immunizations at six-week intervals with autologous monocyte-derived dendritic cells (MD-DC) loaded with heat-inactivated autologous HIV in 12 HIV infected patients who had been receiving highly active antiretroviral therapy (HAART) since early chronic infection. Autologous HIV was concentrated from plasma (1,500 ml) obtained by plasmapheresis after a 3-month HAART interruption (STOP1) performed 78 weeks before therapeutic immunizations, and HAART was discontinued again (STOP2) after therapeutic immunization. There was a decrease of set-point plasma viral load (PVL) >= 0.5 log after 24 weeks off HAART in 4 out of 12 patients. In addition, we observed a significant lengthening in mean doubling time of PVL rebound (p= 0.01), and significant decreases in the area under the curve of PVL rebound (p= 0.02) and in the mean peak PVL (p= 0.004) during the 12 weeks after STOP 2 compared with STOP1. This virological response was associated with a weak but significant increase in HIV-1 specific CD4 lymphoproliferative response, and with changes in HIV-1 specific CD8+ T-cell responses in peripheral blood and in lymphoid CTL cells after immunization. In lymphoid tissue, we also observed a trend towards a better control of HIV-1 replication coupled with an increase of CD4+ and CTL cells. No significant virological or immunological changes occurred in controls. We show that a therapeutic vaccine with autologous MD-DC pulsed with heat inactivated autologous HIV-1 is feasible, safe and well tolerated and elicited weak and transient cellular immune responses against HIV, associated with a partial and transient control of HIV replication in some patients. we hypothesized that a DC vaccine pulsed with higher amount of autologous virus obtained by culture could be more effective than the vaccine we used.

Official Title
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Phase II Study of Autologous Myeloid Dendritic Cells as a Cellular Adjuvant for a Therapeutic HIV-1 Vaccine in Early Stage HIV-1+ Patients (DCV-2).

Conditions
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HIV Infections

Intervention / Treatment
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* Biological: Dendritic cell vaccine
* Biological: non pulsed dendritic cell untreated patients
* Biological: pulsed dendritic cell vaccine
* Biological: dendritic cell vaccine
* Biological: non pulsed dendritic cell vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed HIV infection CD4 > 450 x 10 6 /L baseline VL >10,000 c/ml before any HAART Part I, patients off HAART at least during 6 months Part II, Patients on HAART with PVL < 200 copies/ml at least during 6 months Written informed consent . Exclusion Criteria: Patients with failure to HAART Patients with B or C symptoms (CDC classification 1993). Age < 18 years old. Pregnant or breastfeeding women Patients with baseline creatinin > 2.5 mg/dl Patients with baseline GOT/GPT > 250 UI/L

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pulsed dendritic cells untreated patients<br>Untreated patients receiving a dendritic cell based vaccine pulsed with autologous heat iactivated virus | Biological: Dendritic cell vaccine<br>* 107 DC subcutaneous 3 doses every 2 weeks<br>|
| Placebo Comparator: non pulsed dendritic cells untreated patients<br> | Biological: non pulsed dendritic cell untreated patients<br>* 107 DC subcutaneous 3 doses every 2 weeks<br>|
| Active Comparator: pulsed dendritic cell treated patient<br>treated patients will be immunized with a dendritic cell vaccine pulsed with heat inactivated autologous virus immediately before art interruption | Biological: pulsed dendritic cell vaccine<br>* 107 DC subcutaneous 3 doses every 2 weeks<br>|
| Active Comparator: pulsed dendritic cell in treated patients<br>patients will be immunized with a dendritic cell vaccine pulsed with heat inactivted autologous virus immediately after interruption of art | Biological: dendritic cell vaccine<br>* 107 DC subcutaneous 3 doses every 2 weeks<br>|
| Placebo Comparator: non pulsed dendritic cells<br> | Biological: non pulsed dendritic cell vaccine<br>* 107 DC subcutaneous 3 doses every 2 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of steady state viremia (so-called viral set point) after 6-12 months after vaccination with viremia before HAART. |  | 6 and 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion with evidence of HIV-specific CTL comparing end of immune-based therapy, and end of trial (week 48) with start of immune-based therapy. |  | 6 and 12 months | 
| Proportion with evidence of HIV-specific T-cell proliferative response comparing end of immune-based therapy, and end of trial (week 48) with start of immune-based therapy. |  | 6 and 12 months | 
| Proportion with evidence of HIV-specific neutralizing activity of serum comparing end of immune-based therapy, and end of trial (week 48) with start of immune-based therapy. |  | 6 and 12 months | 
| HIV-1 specific CTL responses in lymphoid tissue |  | 0 and 6 months | 
| DC Migration |  | 0 and 2 weeks | 
| Viral load in semen and vaginal secretions |  | 0 and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV Infection, Dendritic cell vaccine, Autologous virus, Heat inactivated, HIV Therapeutic Vaccine