Mechanism of Action: Therapeutic vaccine. AGS-004 is a therapeutic HIV vaccine based on dendritic cells (DCs). Therapeutic vaccines are being investigated as an immunotherapeutic approach to correcting HIV-associated immune dysfunction, such as impaired DC responses to HIV and suboptimal adaptive immune responses (including HIV-specific T cell responses).5-8 A therapeutic vaccine may potentially increase the effectiveness of ART, simplify ART regimens, or allow for periodic structured treatment interruptions. A successful therapeutic vaccine would either completely eradicate the virus or improve an individual’s immune response to the point where it could suppress viral replication without ART. In either case, a therapeutic vaccine would help to circumvent a lifetime of ART.9
AGS-004 can potentially overcome the deficiencies in DC function that arise during HIV infection. AGS-004 is produced from autologous monocyte-derived DCs that are electroporated with RNA that encodes CD40L (which is required for DC maturation) and the HIV antigens Gag, Vpr, Rev, and Nef, which are derived from an individual’s pre-ART plasma. DCs contained in the AGS-004 final product are fully mature. When administered, these DCs are functioning, antigen-presenting cells capable of stimulating HIV-specific CD8 cytotoxic T lymphocyte (CTL) responses without activating CD4 cells.3,6,8,10-13 Recently, a new method of manufacturing AGS-004 has been employed in a clinical study. This process uses HIV obtained from an individual’s latent viral reservoir, removing the need for pre-ART plasma collection and possibly resulting in a more targeted immune response.14,15
AGS-004 is being developed because it has the potential to control viral replication without ART and to eradicate HIV when used in combination with a latency-reversing agent plus ART.4,16-18
Study Identifiers: IGHID 11424; VORVAX; NCT02707900
Sponsor: Cynthia L Gay, MD
Status: This study is currently recruiting participants.
Study Purpose: The VORVAX trial is an open-label pilot study evaluating the safety of AGS-004 when combined with vorinostat (a latency-reversing agent). The trial will also evaluate this combination’s ability to (1) reactivate latent HIV, (2) generate an HIV-specific immune response, and (3) clear persistent virus in participants on continuous ART.
- Participants are adults with HIV who have been on ART for at least 6 months and who have been on a potent ART regimen for 24 weeks prior to study entry. A potent ART regimen is defined as at least 2 NRTIs/NtRTIs plus an NNRTI, INSTI, or a PI.
- At screening, participants have CD4 cell counts ≥300 cells/mm3 and HIV RNA <50 copies/mL. Participants have also had HIV RNA <50 copies/mL for the previous 6 months.
: All participants will remain on their background ART during the study and will receive treatment as follows:
- Participants will receive a single oral dose of vorinostat 400 mg. If there is a significant increase in resting cell-associated RNA and no clinically significant adverse events (AEs) after the first vorinostat dose, then 2 paired oral doses of vorinostat 400 mg will be administered.
- Participants will receive 4 doses of AGS-004 administered every 3 weeks. Each AGS-004 dose will be delivered as 3 intradermal injections of AGS-004 0.2 mL (0.6 mL total volume per dose, for a total of 1.2 x 107 viable cells).
- Approximately 7 to 10 days after the fourth treatment of AGS-004, participants will receive 10 oral doses of vorinostat 400 mg administered at 72-hour intervals.
- Participants will receive a second series of 4 intradermal AGS-004 doses followed by 10 oral doses of vorinostat 400 mg.15,17,18
: AGS-004-001; CTN #239; NCT00672191
: Argos Therapeutics
: This study has been completed.
: AGS-004-001 was an open-label study that assessed AGS-004’s safety, immunogenicity, and ability to control HIV replication during an analytical treatment interruption (ATI).
- Participants were adults who had chronic HIV infection and who had been on their first ART regimens for at least 3 months.
- Participants had HIV RNA <50 copies/mL for at least 90 days prior to screening and had pre-ART plasma HIV RNA ≥15,000 copies/mL at the time plasma was archived.
- Participants had CD4 counts ≥450 cells/mm3 for at least 90 days prior to screening and had pre-ART nadir CD4 counts ≥200 cells/mm3.
: While on ART, all participants received injections of AGS-004 every 4 weeks for a total of 4 doses. Participants then underwent a 12-week ATI, during which they received 2 monthly doses of AGS-004. Participants could continue on treatment interruption and receive additional doses of AGS-004 if their viral loads remained below 10,000 copies/mL and their CD4 counts were maintained above 350 cells/mm3
Selected Study Results
: AGS-004-003; NCT01069809
: Argos Therapeutics
: This study has been completed.
: The purpose of AGS-004-003 was to determine the safety and efficacy of AGS-004 in controlling HIV replication during an ATI.
- Participants were adults who had chronic HIV infection and who had been on a stable ART regimen for at least 3 months prior to screening.
- Participants had HIV RNA ≤200 copies/mL for at least 3 months prior to study entry and had HIV RNA <50 copies/mL at screening.
- Participants had CD4 counts ≥450 cells/mm3 at screening and had nadir CD4 counts ≥200 cells/mm3.
: Participants were randomized to receive either AGS-004 or placebo, each administered as intradermal injections every 4 weeks for a total of 4 doses, while on ART. At Week 16, a 12-week ATI was undertaken, during which participants continued to receive monthly doses of AGS-004. Participants whose viral loads remained under 10,000 copies/mL and who maintained CD4 counts above 350 cells/mm3
could continue the ATI past 12 weeks.
A single arm consisting of participants who initiated ART during the acute phase of HIV infection was added to this study. Dosing for this arm was open-label and was done in the same way as in the chronically infected arm. Participants in the acute infection cohort, however, had to demonstrate a positive immune response in order to become eligible to enter the 12-week ATI.4,12,24-26
Selected Study Results
Additional early-phase clinical trials (NCT02042248
) evaluating AGS-004 have also been completed.16,27
In the AGS-004-001 study (NCT00672191
), AGS-004–related AEs were primarily mild injection site reactions. There were no reports of Grade 3 or higher AEs or serious adverse events (SAEs) associated with AGS-004 treatment. No deaths or study drug discontinuations due to an AE occurred. There were no notable changes in autoimmunity or other laboratory parameters. There was no notable difference in the incidence of AEs when comparing the period of ATI to the period of AGS-004 plus ART. During treatment interruption, the number of AGS-004–related AEs did not increase and no AIDS-related events were reported.19,21
In the Phase IIb AGS-004-003 study (NCT01069809
), 52 participants received either AGS-004 (n = 35) or placebo (n = 17). There was no difference in the number of severe AEs and AEs between treatment groups. No severe AEs or SAEs were considered related to AGS-004. The most common AE was mild (Grade 1) local injection site reactions, reported by 72% of participants receiving AGS-004 and 82% of participants receiving placebo. Additional AEs that may have been related to AGS-004 included headache, nausea, depression, dizziness, increase in vivid dreams, lymphadenopathy, and skin rash. When comparing the period of ATI versus the period of AGS-004 plus ART, there was no notable difference in incidence of AEs.4,24,25
AGS-004 drug interactions are currently unknown.
- United States National Library of Medicine. ChemIDplus Advanced. Available at: https://chem.sis.nlm.nih.gov/chemidplus/rn/1807497-10-4. Last accessed on October 17, 2017.
- Frick M, Gaudino A, Harrington M, et al. Treatment Action Group. 2017 pipeline report. July 2017. Available at: http://www.pipelinereport.org/sites/default/files/2017%20Pipeline%20Report%20Final.pdf. Last accessed on October 17, 2017.
- Argos Therapeutics website. HIV clinical trials. Available at: http://www.argostherapeutics.com/hiv-clinical-trials/. Last accessed on October 17, 2017.
- Argos Therapeutics. A Randomized, Double-Blind, Phase 2B Study Testing the Efficacy and Safety of AGS-004 on Host Control of HIV Replication During Analytical Treatment Interruption. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 16, 2010. NLM Identifier: NCT01069809. Available at: https://clinicaltrials.gov/ct2/show/NCT01069809. Last accessed on October 17, 2017.
- Lederman MM, Rodriguez B, Sieg S. Immunopathogenesis of HIV Infection. In: Coffey S and Volberding P, eds. HIV InSite Knowledge Base. University of California San Francisco; 2004. Available at: http://hivinsite.ucsf.edu/InSite?page=kb-00&doc=kb-02-01-04. Last accessed on October 17, 2017.
- Miller E and Bhardwaj N. Advances in dendritic cell immunotherapies for HIV-1 infection. Expert Opin Biol Ther. 2014; 14(11): 1545-1549. Available at: http://www.tandfonline.com/doi/full/10.1517/14712598.2014.950652. Last accessed on October 17, 2017.
- Smith PL, Tanner H, Dalgleish A. Developments in HIV-1 immunotherapy and therapeutic vaccination. F1000Prime Rep. 2014 Jun 2; 6:43. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047951/. Last accessed on October 17, 2017.
- Routy JP, Boulassel MR, Yassine-Diab B, et al. Immunologic activity and safety of autologous HIV RNA-electroporated dendritic cells in HIV-1 infected patients receiving antiretroviral therapy. Clin Immunol. 2010 Feb; 134(2):140-7. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818410/. Last accessed on October 17, 2017.
- Graziani GM and Angel JB. Evaluating the efficacy of therapeutic HIV vaccines through analytical treatment interruptions. J Int AIDS Soc. 2015; 18(1): 20497. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641978/. Last accessed on October 17, 2017.
- Argos Therapeutics website. About the Arcelis® technology platform. Available at: http://www.argostherapeutics.com/precision-immunotherapy/arcelis-platform/. Last accessed on October 17, 2017.
- GeMCRIS: Genetic Modification Clinical Research Information System, Version 6.2. Gene Transfer Protocol Reports: Protocol Number 0912-1015. Scientific Abstract of Protocol AGS-004-003. Available at: https://www.gemcris.od.nih.gov/Abstracts/1015_s.pdf. Last accessed on October 17, 2017.
- Gay C, Archin N, Tcherepanova I, et al. Immunogenicity of AGS-004 Dendritic Cell Therapy in Patients Treated during Acute HIV Infection. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA. Poster 344. Available at: http://www.croiconference.org/sites/default/files/posters/344.pdf. Last accessed on October 17, 2017.
- Healey D, Yassine Diab B, Coutsinos Z, et al. Immunologic activity of a fully autologous dendritic cell immunotherapy for the treatment of HIV-1 infected subjects. Abstract presented at: International AIDS Conference (IAS); July 18-23, 2010; Vienna, Austria. Abstract THPE0181. Available at: http://www.abstract-archive.org/Abstract/Share/5965. Last accessed on October 17, 2017.
- Krisko J, Archin NM, Horvatinovich J, et al. Development of an autologous HIV outgrowth process for the manufacture of targeted immunotherapy for latent reservoir clearance. Abstract presented at: Strategies for an HIV Cure 2016; November 14-16, 2016; Bethesda, MD. Abstract 45. Available at: https://respond.niaid.nih.gov/conferences/hivcuremeeting2016/Documents/508%20Poster%20Abstracts.pdf. Last accessed on October 17, 2017.
- Argos Therapeutics: Press release, dated September 6, 2017. Argos announces first dosing of HIV patient with AGS-004 derived from the latent viral reservoir. Available at: http://ir.argostherapeutics.com/releasedetail.cfm?ReleaseID=1039288. Last accessed on October 17, 2017.
- Cynthia L Gay, MD. IGHID 1309 - A Phase I Study to Evaluate the Kinetics of the Immunologic Response and Virologic Impact of AGS-004 in HIV-Infected Individuals Suppressed on Antiretroviral Therapy Initiated During Acute and Chronic HIV Infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on January 17, 2014. NLM Identifier: NCT02042248. Available at: https://clinicaltrials.gov/ct2/show/NCT02042248. Last accessed on October 17, 2017.
- Cynthia L Gay, MD. IGHID 11424 - A Pilot Trial of the Effect of Vorinostat and AGS-004 on Persistent HIV-1 Infection (The VOR VAX Study). In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on March 3, 2016. NLM Identifier: NCT02707900. Available at: https://clinicaltrials.gov/ct2/show/NCT02707900. Last accessed on October 17, 2017.
- Argos Therapeutics: Press release, dated April 1, 2015. NIH Funds Study of Fully Personalized Immunotherapy AGS-004 Combined With a Latency Reversing Therapy for the Treatment of HIV. Available at: http://ir.argostherapeutics.com/releasedetail.cfm?releaseid=904466. Last accessed on October 17, 2017.
- Argos Therapeutics. A Phase II Study Testing the Activity and Safety of AGS-004 as an Immunotherapeutic in Successfully ART-Treated Subjects Infected With HIV-1 in Combination With ART Followed by ART Interruption. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on May 5, 2008. NLM Identifier: NCT00672191. Available at: https://clinicaltrials.gov/ct2/show/NCT00672191. Last accessed on October 17, 2017.
- DeBenedette M, Tcherepanova I, Gamble A, et al. Immune Function and Viral Load Post AGS-004 Administration to Chronic HIV*Subjects Undergoing STI. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); March 3-6, 2014; Boston, MA. Abstract 343. Available at: http://www.croiconference.org/sessions/immune-function-and-viral-load-post-ags-004-administration-chronic-hivsubjects-undergoing. Last accessed on October 17, 2017.
- Routy J-P, Angel J, Vezina S, et al. Final Analysis of a Phase 2 Study of an Autologous Dendritic Cell Immunotherapy (AGS-004) Showed Positive Outcomes in Primary Endpoint of Viral Load Control, and Favorable Safety and Immunogenicity Profile, in Subjects Undergoing Structured Treatment Interruption of ART. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 27-March 2, 2011; Boston, MA. Poster H-114. Available at: http://www.argostherapeutics.com/literature/2011-AGS-004-001-CROI-poster-Final.pdf. Last accessed on October 3, 2016.
- Tcherepanova I, Harris J, Horvatinovich J, et al. Autologous dendritic cell-based therapy modulates proviral DNA levels in chronically HIV-infected subjects. Abstract presented at: AIDS Vaccine 2013; October 7-10, 2013; Barcelona, Spain. Abstract P04.35 LB. Available at: http://www.vaccineenterprise.org/conference/2013/sites/default/files/AIDS-Vaccine-2013-Abstract-Book.pdf. Last accessed on October 17, 2017.
- Routy J-P. Safety and viral load changes in HIV-1 infected subjects treated with autologous dendritic cell immune therapy following ART discontinuation (CTN #239). Slides presented at: AIDS Vaccine 2009; October 19-22, 2009; Paris, France. Available at: http://www.vaccineenterprise.org/conference_archive/2009/pdf_slides/Jean-Pierre-Routy.pdf. Last accessed on October 17, 2017.
- Jacobson JM, Routy JP, Welles S, et al. Dendritic cell immunotherapy for HIV-1 infection using autologous HIV-1 RNA: a randomized, double-blind, placebo-controlled clinical trial. J Acquir Immune Defic Syndr. 2016 May 1; 72(1): 31-38. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836975/. Last accessed on October 17, 2017.
- ARGOS THERAPEUTICS INC: FORM 10-K (Annual Report), Filed 03/30/16 for the Period Ending 12/31/15. Available at: http://files.shareholder.com/downloads/AMDA-TSH5S/2878656665x0xS1171843-16-8919/1105533/filing.pdf. Last accessed on October 17, 2017.
- Gay CL, DeBenedette MA, Tcherepanova IY, et al. Immunogenicity of AGS-004 dendritic cell therapy in patients treated during acute HIV infection. AIDS Res Hum Retroviruses. 2017 Jun 21. [Epub ahead of print]. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28636433. Last accessed on October 17, 2017.
- McGill University Health Center. A Pilot Study (Phase I/II) Testing the Immunologic Activity and Safety of AGS-004, an Autologous HIV Immunotherapeutic, in HIV-Infected Adults on HAART. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on September 25, 2006. NLM Identifier: NCT00381212. Available at: https://clinicaltrials.gov/ct2/show/NCT00381212. Last accessed on October 17, 2017.
Last Reviewed: October 17, 2017