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 bypass defects in DC function. Through the technology of loading an individual’s DCs with autologous HIV antigen in an ex vivo setting, AGS-004 can induce HIV-specific immune responses matched to an individual’s unique virus population. AGS-004 is produced from autologous monocyte-derived DCs that are electroporated with RNA encoding CD40L (required for DC maturation) and 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 exclusively inducing HIV-specific CD8 cytotoxic T lymphocyte (CTL) responses without activating CD4 cells.6,8,10-13
AGS-004 is being developed for its potential to control viral replication without ART and to eradicate HIV when used in combination with a latency-reversing agent plus ART.4,14-16
Study Identifiers: IGHID 11424; VORVAX; NCT02707900
Sponsor: Cynthia L Gay, MD
Study Purpose: The VORVAX trial is an open-label pilot study evaluating the safety of AGS-004 combined with vorinostat (a latency-reversing agent) and the ability of AGS-004 combined with vorinostat to (1) reactivate latent HIV, (2) generate an HIV-specific immune response, and (3) clear persistent virus in participants on continuous ART.
- Participants are HIV-infected, treatment-experienced adults who have been on ART for at least 6 months and who have been on a “potent” ART regimen throughout the 24 weeks prior to study entry.
- Participants have had HIV RNA <50 copies/mL for the past 6 months and at screening and CD4 cell counts ≥300 cells/mm3 at screening.
Dosing: All participants will remain on their background ART throughout the duration of the study and will be dosed 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
* This study is currently recruiting participants.
Study Identifiers: AGS-004-001; CTN #239; NCT00672191
Sponsor: Argos Therapeutics
Study Purpose: AGS-004-001 was an open-label study that assessed AGS-004’s safety, immunogenicity, and ability to control HIV replication during analytical treatment interruption (ATI).
- Participants were treatment-experienced adults who had chronic HIV infection and 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 pre-ART plasma HIV RNA ≥15,000 copies/mL at the time plasma was archived before starting ART.
- Participants had CD4 counts ≥450 cells/mm3 for at least 90 days prior to screening and pre-ART nadir CD4 counts ≥200 cells/mm3.
Dosing: All participants, while on ART, received injections of AGS-004 every 4 weeks for a total of 4 doses. Participants then underwent a 12-week ATI, during which time 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/mm3.18-22
Selected Study Results:
Study Identifiers: AGS-004-003; NCT01069809
Sponsor: Argos Therapeutics
Study Purpose: The purpose of AGS-004-003 was to determine the safety and effectiveness of AGS-004 in controlling HIV replication during an ATI.
- Participants were treatment-experienced adults who had chronic HIV infection and had been on a stable ART regimen for at least 3 months prior to screening.
- Participants had HIV RNA ≤400 copies/mL for at least 2 months prior to screening and ≤50 copies/mL at screening.
- Participants had CD4 counts ≥450 cells/mm3 at screening and pre-ART nadir CD4 counts ≥200 cells/mm3.
Dosing: 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 time participants continued to receive monthly doses of AGS-004. Participants who demonstrated viral load control under 10,000 copies/mL and maintained CD4 counts above 350 cells/mm3 could continue the ATI past 12 weeks.4,23,24
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 done in the same manner 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.12,23,24
Selected Study Results:
Additional early-phase clinical trials (NCT02042248
) evaluating AGS-004 have also been undertaken.14,25
In the AGS-004-001 study (NCT00672191
), AGS-004-related AEs that occurred were primarily mild injection site reactions. There were no reports of Grade 3 or higher AEs, serious adverse events (SAEs), deaths, or study drug discontinuations due to an AE. No clinically significant changes in autoimmunity or other laboratory parameters occurred. When comparing the period of ART treatment interruption versus the period of AGS-004 plus ART, there was no notable difference in incidence of AEs. During the treatment interruption, there was no increase in AGS-004-related AEs and no AIDS-related events reported.18,20
In the Phase IIb AGS-004-003 study (NCT01069809
), the most common AE was mild (Grade 1) local injection site reactions. The company developing AGS-004 reported no SAEs related to AGS-004. Also, when comparing the period of ART treatment interruption versus the period of AGS-004 plus ART, there was no notable difference in incidence of AEs.4,23,24
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 3, 2016.
- Clayden P, Collins S, Frick M, et al. HIV i-BASE/Treatment Action Group. 2016 Pipeline Report. July 2016. Available at: http://www.pipelinereport.org/sites/default/files/2016%20Pipeline%20Report%20Full_0.pdf. Last accessed on October 3, 2016.
- Argos Therapeutics website. Product Pipeline. Available at: http://www.argostherapeutics.com/platform-and-pipeline/product-pipeline/. Last accessed on October 3, 2016.
- 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 3, 2016.
- 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 3, 2016.
- 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 3, 2016.
- Smith PL, Tanner H, Dalgleish A. Developments in HIV-1 immunotherapy and therapeutic vaccination. F1000Prime Rep. 2014 Jun 2; 6:43. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4047951/. Last accessed on October 3, 2016.
- 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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2818410/. Last accessed on October 3, 2016.
- 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: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641978/. Last accessed on October 3, 2016.
- Argos Therapeutics website. Therapeutic Platforms. Available at: http://www.argostherapeutics.com/platform-and-pipeline/therapeutic-platforms/. Last accessed on October 3, 2016.
- 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 3, 2016.
- 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: 21st 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 3, 2016.
- 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: 18th 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 3, 2016.
- Cynthia L Gay, MD. IGHID 1309 - A Phase I/II 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 2, 2016.
- 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 3, 2016.
- 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 3, 2016.
- Argos Therapeutics: Press release, dated July 14, 2016. Argos Therapeutics Announces First Patient Dosed in Stage 2 of Adult Eradication Trial of AGS-004 in the Treatment of HIV. Available at: http://ir.argostherapeutics.com/releasedetail.cfm?releaseid=979564. Last accessed on October 3, 2016.
- 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 3, 2016.
- 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: 21st 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 3, 2016.
- 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: 18th 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. Poster presented at: AIDS Vaccine 2013; October 7-10, 2013; Barcelona, Spain. Poster PO4.35 LB. Available at: http://www.argostherapeutics.com/literature/Tcherepanova-Barcelona-Final.pdf. Last accessed on October 3, 2016.
- 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 3, 2016.
- 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): 31-8. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26751016. Last accessed on October 3, 2016.
- 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 3, 2016.
- 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 3, 2016.
Last Reviewed: October 3, 2016