A randomized therapeutic vaccine trial of canarypox-HIV-pulsed dendritic cells vs. canarypox-HIV alone in HIV-1-infected patients on antiretroviral therapy

Abstract

Targeting canarypox (CP)-HIV vaccine to dendritic cells (DCs) elicits anti-HIV-1 immune responses in vitro. We conducted a phase I/II clinical trial to evaluate whether adding DC to a CP-HIV vaccine improved virologic control during analytic treatment interruption (ATI) in HIV-1-infected subjects. Twenty-nine subjects on suppressive antiretroviral therapy were randomized to vaccination with autologous DCs infected with CP-HIV + keyhole limpet hemocyanin (KLH) (arm A, n = 14) or CP-HIV + KLH alone (arm B, n = 15). The mean viral load (VL) setpoint during ATI did not differ between subjects in arms A and B. A higher percentage of subjects in the DC group had a VL setpoint <5000 c/mL during ATI (4/13 or 31% in arm A compared with 0/13 in arm B, p = 0.096), but virologic control was transient. Subjects in arm A had a greater increase in KLH lymphoproliferative response than subjects in arm B; however, summed ELISPOT responses to HIV-1 antigens did not differ by treatment arm. We conclude that a DC-CP-HIV vaccine is well-tolerated in HIV-1-infected patients, but does not lower VL setpoint during ATI compared with CP-HIV alone. New methods to enhance the immunogenicity and antiviral efficacy of DC-based vaccines for HIV-1 infection are needed.

HIV-specific CD8+ T cells from HIV+ individuals receiving HAART can be expanded ex vivo to augment systemic and mucosal immunity in vivo

“…Many HIV immunogens have been developed and administered to HIVinfected individuals in whom HAART was initiated early in the course of disease, with the intent of subsequently discontinuing HAART. 15,17,49 Disappointingly, no correlation was found between the number and breadth of CD8 ϩ T-cell responses after vaccination and the control of HIV viral replication after the interruption of HAART. There are many potential explanations for this outcome, but ultimately the results suggest the vaccine stimulus was inadequate.…”

Dendritic cell based vaccines for HIV infection

“…11,37,38 Some studies in animal models suggest that animals immunized with DCs loaded with HIV-1 viral lysate, envelope glycoproteins or inactivated virus mount a potent immune response against HIV-1. [39][40][41]42 Although it has been performed at least 13 published clinical trials of DC-based immunotherapy for HIV infection in humans [43][44][45][46][47][48][49][50]55 (reviewed in ref. 9), most of them were non-controlled, nonrandomized studies.…”

“…However, only five of these studies reported virological responses to immunization, 44,45,51,52,55 three have not assessed virological responses 47,50,53 and five failed to show any response. 43,46,48,49,54 Recently, our group reported the results of a blinded placebo controlled trial of a therapeutic vaccine using autologous MD-DC pulsed with autologous heatinactivated whole HIV. We immunized 36 patients on cART with high CD4 T-cell counts with 3 doses of MD-DC cells (n = 24) or with non-pulsed MD-DC (n = 12).…”

“…48 We have reported that MVA-B (MVA expressing the HIV-1 genes Env-Gag-Pol-Nef of clade B) infected MDDC co-cultured with autologous T lymphocytes induced a highly functional HIV-specific CD8 + T-cell response including proliferation, secretion of IFNgamma, IL-2, TNF-α, MIP-1beta, MIP1alpha, RANTES, and IL-6, and strong cytotoxic activity against autologous HIV-1-infected CD4 + T lymphocytes. Ghandi et al 48 conducted a phase I/II clinical trial to evaluate whether adding MD-DCs to a Canarypox-HIV vaccine improved virologic control as compared with Canarypox-HIV vaccine alone during analytic treatment interruption in HIV-1-infected subjects. They found that higher percentage of subjects in the DC group had a VL setpoint < 5000 c/ mL during cART interruption, but virologic control was transient.…”

“Wrapped Up” Vaccines in the Context of HIV-1 Immunotherapy

“…Such vaccines would elicit or boost HIV specific cytotoxic T cells (CTLs) to eliminate infected cells and CD4 + T cells, which can help to induce and maintain B cell and CD8 + T cells responses [92]. Several strategies are currently under investigation to establish effective T cell responses in either a preventive or therapeutic setting either based on protein [93,94] or peptide [95] vaccinations, virus like particles (VPLs) [96], DNA vaccination using viral vectors [97,98], prime-boost vaccinations [99,100] or DC-based vaccines [101][102][103][104][105][106][107][108][109].…”