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

Jeffrey M. Jacobson, Jean Pierre Routy, Seth Welles, Mark DeBenedette, Irina Tcherepanova, Jonathan B. Angel, David Asmuth, David K. Stein, Jean Guy Baril, Mehri McKellar, David M. Margolis, Benoit Trottier, Kenneth Wood, Charles Nicolette

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 (DC). METHODS:: This phase IIB, multicenter, 2:1 randomized, double blind, placebo-controlled study enrolled 54 HIV-1-infected patients on antiretroviral therapy (ART) with viral loads (VL) 450 cells/mm, and nadir counts >200 cells/mm, 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 two 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-ART 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 IFN-γ, IL-2, TNF-α, CD107a, and granzyme b expression was measured by multicolor flow cytometry, a greater percentage of AGS-004 than of placebo recipients had multifunctional CTL responses induced in the CD28+/CD45RA- CD8 effector/memory T-cell population to DCs 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 to placebo.

Original languageEnglish (US)
JournalJournal of Acquired Immune Deficiency Syndromes
DOIs
StateAccepted/In press - Jan 8 2016

Fingerprint

Controlled Clinical Trials
Immunotherapy
Dendritic Cells
HIV Infections
HIV-1
Viral Load
Placebos
RNA
Antiviral Agents
T-Lymphocytes
Therapeutics
Granzymes
Intradermal Injections
Consensus Sequence
Autoantigens
Interleukin-2
Flow Cytometry
Vaccines
Lymph Nodes
HIV

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Dendritic Cell Immunotherapy for HIV-1 Infection Using Autologous HIV-1 RNA : A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. / Jacobson, Jeffrey M.; Routy, Jean Pierre; Welles, Seth; DeBenedette, Mark; Tcherepanova, Irina; Angel, Jonathan B.; Asmuth, David; Stein, David K.; Baril, Jean Guy; McKellar, Mehri; Margolis, David M.; Trottier, Benoit; Wood, Kenneth; Nicolette, Charles.

In: Journal of Acquired Immune Deficiency Syndromes, 08.01.2016.

Research output: Contribution to journalArticle

Jacobson, JM, Routy, JP, Welles, S, DeBenedette, M, Tcherepanova, I, Angel, JB, Asmuth, D, Stein, DK, Baril, JG, McKellar, M, Margolis, DM, Trottier, B, Wood, K & Nicolette, C 2016, 'Dendritic Cell Immunotherapy for HIV-1 Infection Using Autologous HIV-1 RNA: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial', Journal of Acquired Immune Deficiency Syndromes. https://doi.org/10.1097/QAI.0000000000000926
Jacobson, Jeffrey M. ; Routy, Jean Pierre ; Welles, Seth ; DeBenedette, Mark ; Tcherepanova, Irina ; Angel, Jonathan B. ; Asmuth, David ; Stein, David K. ; Baril, Jean Guy ; McKellar, Mehri ; Margolis, David M. ; Trottier, Benoit ; Wood, Kenneth ; Nicolette, Charles. / Dendritic Cell Immunotherapy for HIV-1 Infection Using Autologous HIV-1 RNA : A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. In: Journal of Acquired Immune Deficiency Syndromes. 2016.
@article{d360b48a16c54aaa8d74dbe605e478fc,
title = "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 (DC). METHODS:: This phase IIB, multicenter, 2:1 randomized, double blind, placebo-controlled study enrolled 54 HIV-1-infected patients on antiretroviral therapy (ART) with viral loads (VL) 450 cells/mm, and nadir counts >200 cells/mm, 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 two 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-ART 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 IFN-γ, IL-2, TNF-α, CD107a, and granzyme b expression was measured by multicolor flow cytometry, a greater percentage of AGS-004 than of placebo recipients had multifunctional CTL responses induced in the CD28+/CD45RA- CD8 effector/memory T-cell population to DCs 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 to placebo.",
author = "Jacobson, {Jeffrey M.} and Routy, {Jean Pierre} and Seth Welles and Mark DeBenedette and Irina Tcherepanova and Angel, {Jonathan B.} and David Asmuth and Stein, {David K.} and Baril, {Jean Guy} and Mehri McKellar and Margolis, {David M.} and Benoit Trottier and Kenneth Wood and Charles Nicolette",
year = "2016",
month = "1",
day = "8",
doi = "10.1097/QAI.0000000000000926",
language = "English (US)",
journal = "Journal of acquired immune deficiency syndromes (1999)",
issn = "1525-4135",
publisher = "Lippincott Williams and Wilkins",

}

TY - JOUR

T1 - Dendritic Cell Immunotherapy for HIV-1 Infection Using Autologous HIV-1 RNA

T2 - A Randomized, Double-Blind, Placebo-Controlled Clinical Trial

AU - Jacobson, Jeffrey M.

AU - Routy, Jean Pierre

AU - Welles, Seth

AU - DeBenedette, Mark

AU - Tcherepanova, Irina

AU - Angel, Jonathan B.

AU - Asmuth, David

AU - Stein, David K.

AU - Baril, Jean Guy

AU - McKellar, Mehri

AU - Margolis, David M.

AU - Trottier, Benoit

AU - Wood, Kenneth

AU - Nicolette, Charles

PY - 2016/1/8

Y1 - 2016/1/8

N2 - 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 (DC). METHODS:: This phase IIB, multicenter, 2:1 randomized, double blind, placebo-controlled study enrolled 54 HIV-1-infected patients on antiretroviral therapy (ART) with viral loads (VL) 450 cells/mm, and nadir counts >200 cells/mm, 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 two 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-ART 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 IFN-γ, IL-2, TNF-α, CD107a, and granzyme b expression was measured by multicolor flow cytometry, a greater percentage of AGS-004 than of placebo recipients had multifunctional CTL responses induced in the CD28+/CD45RA- CD8 effector/memory T-cell population to DCs 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 to placebo.

AB - 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 (DC). METHODS:: This phase IIB, multicenter, 2:1 randomized, double blind, placebo-controlled study enrolled 54 HIV-1-infected patients on antiretroviral therapy (ART) with viral loads (VL) 450 cells/mm, and nadir counts >200 cells/mm, 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 two 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-ART 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 IFN-γ, IL-2, TNF-α, CD107a, and granzyme b expression was measured by multicolor flow cytometry, a greater percentage of AGS-004 than of placebo recipients had multifunctional CTL responses induced in the CD28+/CD45RA- CD8 effector/memory T-cell population to DCs 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 to placebo.

UR - http://www.scopus.com/inward/record.url?scp=84954509568&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84954509568&partnerID=8YFLogxK

U2 - 10.1097/QAI.0000000000000926

DO - 10.1097/QAI.0000000000000926

M3 - Article

C2 - 26751016

AN - SCOPUS:84954509568

JO - Journal of acquired immune deficiency syndromes (1999)

JF - Journal of acquired immune deficiency syndromes (1999)

SN - 1525-4135

ER -