Dendritic Cell Immunotherapy for HIV-1 Infection Using Autologous HIV-1 RNA: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Abstract

Background: The genomic heterogeneity of HIV-1 impedes the ability of consensus sequences in vaccines to elicit effective antiviral immune responses. AGS-004 amplifies translation-competent RNA molecules encoding for Gag, Rev, Vpr, and Nef from the patient's autologous virus and loads them into dendritic cells.

Methods: This phase IIB, multicenter, 2:1 randomized, double-blind, placebo-controlled study enrolled 54 HIV-1-infected patients on antiretroviral therapy with viral loads (VLs) <50 copies per milliliter, current CD4 T-cell counts >450 cells per cubic millimeter, and nadir counts >200 cells per cubic millimeter, to receive intradermal injections of study product into the axillary lymph node region every 4 weeks. At week 16, a 12-week analytical treatment interruption (ATI) was undertaken.

Results: There was no difference in the end-of-ATI VL (average of values from weeks 11 and 12) between the 2 arms of the study [4.39 (4.17, 4.69) vs. 4.47 (3.76, 4.64) log10 HIV-1 RNA; P = 0.73]. Between arms, no change between pre-antiretroviral therapy VL and the end-of-ATI VL [-0.06 (0.24, -0.32) vs. -0.17 (0.17, -0.32) log10 HIV-1 RNA; P = 0.43] was observed. When interferon-γ, interleukin-2, tumor necrosis factor α, CD107a, and granzyme b expressions were measured by multicolor flow cytometry, a greater percentage of AGS-004 than of placebo recipients had multifunctional cytotoxic T-lymphocyte responses induced in the CD28+/CD45RA-CD8 effector/memory T-cell population to dendritic cells electroporated with autologous antigens. Adverse events consisted of transient, mild (grade 1) local injection site reactions.

Conclusions: Despite the induction of HIV-specific effector/memory CD8 T-cell responses, no antiviral effect was seen after the administration of AGS-004 when compared with placebo.

FIGURE 1

Cell surface Boolean gating of immune monitoring samples. A, Representative immune monitoring sample depicting gate sets to identify CD8⁺ T-cell subsets. CD28 positive and negative cells identified in the CD28 histogram are further subgated on the basis of the expression of CD45RA, CD27, and CCR7. The CD28+/CD45RA− effector memory subset is determined by the expression of CD28 and the absense of CD45RA expression. B, Representative immune monitoring sample depiciting gate sets to identify the six functional markers within the CD28+/CD45RA− effector/memory phenotype.

FIGURE 2

(A) Median plasma HIV-1 RNA copies/ml and (B) median CD4 cell counts over 12-week analytical treatment interruption period. Median plasma HIV-1 values are presented with associated 25% to 75% interquartile ranges. Treatment effect over time was not significant (P =0.58). Median CD4 cell counts are presented with associated 25% to 75% interquartile ranges. Treatment effect over time was was not significant (P >0.05).

FIGURE 2

(A) Median plasma HIV-1 RNA copies/ml and (B) median CD4 cell counts over 12-week analytical treatment interruption period. Median plasma HIV-1 values are presented with associated 25% to 75% interquartile ranges. Treatment effect over time was not significant (P =0.58). Median CD4 cell counts are presented with associated 25% to 75% interquartile ranges. Treatment effect over time was was not significant (P >0.05).

FIGURE 3

Increases in functional CD28+/CD45RA− CTL after in vitro restimulation with AGS-004. The total number of cells/ml expressing any functional marker was determined at each time point. After background subtraction, the value determined at baseline (week 0) was subtracted from week 8, week 18, and week 26 values. Each bar represents a separate subject either receiving AGS-004 (A) or placebo (B).