Immunogenicity of AGS-004 Dendritic Cell Therapy in Patients Treated During Acute HIV Infection

Abstract

AGS-004 consists of matured autologous dendritic cells co-electroporated with in vitro transcribed RNA encoding autologous HIV antigens. In an open-label, single arm sub-study of AGS-004-003, AGS-004 was administered monthly to suppressed participants who started antiretroviral therapy (ART) during acute HIV infection. HIV-1 specific T cell responses were measured by multicolor flow cytometry after 3-4 doses. The frequency of resting CD4+ T-cell infection (RCI) was measured by quantitative viral outgrowth assay. Participants demonstrating increased immune response postvaccination were eligible for analytic treatment interruption (ATI). AGS-004 induced a positive immune response defined as ‡2-fold increase from baseline in the number of multifunctional HIV-1 specific CD28+ /CD45RA -CD8 + effector/memory cytoxic T-lymphocytes (CTLs) in all six participants. All participants underwent ATI with rebound viremia at a median of 29 days. Immune correlates between time to viral rebound and the induction of effector CTLs were determined. Baseline RCI was low in most participants (0.043-0.767 IUPM). One participant had a >2-fold decrease (0.179-0.067 infectious units per million [IUPM]) in RCI at week 10. One participant with the lowest RCI had the longest ATI. AGS-004 dendritic cell administration increased multifunctional HIV-specific CD28 + /CD45RA -CD8 + memory T cell responses in all participants, but did not permit sustained ART interruption. However, greater expansion of CD28 -/CCR7 -/CD45RA -CD8 + effector T cell responses correlated with a longer time to viral rebound. AGS-004 may be a useful tool to augment immune responses in the setting of latency reversal and eradication strategies.

mRNA vaccines — a new era in vaccinology

“…Development of infectious disease vaccines using this approach has been mainly limited to a therapeutic vaccine for HIV-1: HIV-1-infected individuals on highly active antiretroviral therapy were treated with autologous DCs electroporated with mRNA encoding various HIV-1 antigens, and cellular immune responses were evaluated 101–106 . This intervention proved to be safe and elicited antigen-specific CD4 + and CD8 + T cell responses, but no clinical benefit was observed.…”

Assessing the impact of AGS-004, a dendritic cell-based immunotherapy, and vorinostat on persistent HIV-1 Infection

“…AGS-004 is a dendritic cell (DC)-based immunotherapy consisting of matured autologous DCs co-electroporated with in vitro transcribed ribonucleic acid (RNA) encoding autologous HIV antigens (gag, vpr, rev, and nef) plus synthetically derived cluster of differentiation 40 ligand (CD40L) RNA to achieve DC functionality 10 . This vaccine was reported to induce HIV-specific effector/memory CD8 T-cell responses in HIV-infected individuals who had initiated ART during acute or chronic infection [11][12][13] .…”

Ribonucleic Acid Engineering of Dendritic Cells for Therapeutic Vaccination: Ready ‘N Able to Improve Clinical Outcome?

“…In these three trials that evaluated clinical efficacy, no clinical responses were detected. Specifically, there were no indications of efficacy compared to historical controls, no differences in viral RNA levels or CD4+ T-cell counts and no effect on the duration of antiretroviral therapy interruption [100][101][102].…”

“…Three of these trials did not investigate clinical effects [86,98,99]. The remaining three trials involved 77 patients, including a placebo-controlled randomized phase IIb trial on 54 patients [100][101][102]. In these three trials that evaluated clinical efficacy, no clinical responses were detected.…”