drugset / Trial / NCT02042248
A Phase I Study to Evaluate the Immunologic Response and Virologic Impact of AGS-004
Phase 1
Completed
6 enrolled
Cynthia L Gay, MD
Argos Therapeutics · collabNational Institute of Allergy and Infectious Diseases (NIAID) · collab
Non-randomizedParallel-groupOpen-labelTreatment
Summary
The purpose of this study is to: * find out the intensity and duration of the immune response after multiple injections of the investigational study product AGS-004 made from one's own dendritic cells and one's own strain of HIV; * understand the changes in the body's HIV DNA , and HIV-1 RNA in peripheral and resting CD4+ cells prior to and following administration of AGS- 004. * find out if low levels of HIV virus that are not detectable by standard HIV RNA assays will decrease following the administration of AGS-004. * find out if it is safe to give individuals with HIV multiple injections of AGS-004 made from the person's own dendritic cells and their own strain of HIV. * find out if administration of AGS-004 decreases the amount of latent HIV infection in resting CD4 cells
Timeline
- Start
- 2014-03
- Primary completion
- 2016-05
- Completion
- 2016-05
Publications
- Background Finzi D, Hermankova M, Pierson T, Carruth LM, Buck C, Chaisson RE, Quinn TC, Chadwick K, Margolick J, Brookmeyer R, Gallant J, Markowitz M, Ho DD, Richman DD, Siliciano RF. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997 Nov 14;278(5341):1295-300. doi: 10.1126/science.278.5341.1295.
- Background Finzi D, Blankson J, Siliciano JD, Margolick JB, Chadwick K, Pierson T, Smith K, Lisziewicz J, Lori F, Flexner C, Quinn TC, Chaisson RE, Rosenberg E, Walker B, Gange S, Gallant J, Siliciano RF. Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999 May;5(5):512-7. doi: 10.1038/8394.
- Background Chun TW, Stuyver L, Mizell SB, Ehler LA, Mican JA, Baseler M, Lloyd AL, Nowak MA, Fauci AS. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13193-7. doi: 10.1073/pnas.94.24.13193.
- Background Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, Racz P, Tenner-Racz K, Dalesandro M, Scallon BJ, Ghrayeb J, Forman MA, Montefiori DC, Rieber EP, Letvin NL, Reimann KA. Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science. 1999 Feb 5;283(5403):857-60. doi: 10.1126/science.283.5403.857.
- Background Addo MM, Draenert R, Rathod A, Verrill CL, Davis BT, Gandhi RT, Robbins GK, Basgoz NO, Stone DR, Cohen DE, Johnston MN, Flynn T, Wurcel AG, Rosenberg ES, Altfeld M, Walker BD. Fully differentiated HIV-1 specific CD8+ T effector cells are more frequently detectable in controlled than in progressive HIV-1 infection. PLoS One. 2007 Mar 28;2(3):e321. doi: 10.1371/journal.pone.0000321.
- Background Goulder PJ, Watkins DI. HIV and SIV CTL escape: implications for vaccine design. Nat Rev Immunol. 2004 Aug;4(8):630-40. doi: 10.1038/nri1417. No abstract available.
- Background Barouch DH, Kunstman J, Kuroda MJ, Schmitz JE, Santra S, Peyerl FW, Krivulka GR, Beaudry K, Lifton MA, Gorgone DA, Montefiori DC, Lewis MG, Wolinsky SM, Letvin NL. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature. 2002 Jan 17;415(6869):335-9. doi: 10.1038/415335a.
- Background Vaccari M, Mattapallil J, Song K, Tsai WP, Hryniewicz A, Venzon D, Zanetti M, Reimann KA, Roederer M, Franchini G. Reduced protection from simian immunodeficiency virus SIVmac251 infection afforded by memory CD8+ T cells induced by vaccination during CD4+ T-cell deficiency. J Virol. 2008 Oct;82(19):9629-38. doi: 10.1128/JVI.00893-08. Epub 2008 Jul 30.
- Background McNeil AC, Shupert WL, Iyasere CA, Hallahan CW, Mican JA, Davey RT Jr, Connors M. High-level HIV-1 viremia suppresses viral antigen-specific CD4(+) T cell proliferation. Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13878-83. doi: 10.1073/pnas.251539598.
- Background Younes SA, Yassine-Diab B, Dumont AR, Boulassel MR, Grossman Z, Routy JP, Sekaly RP. HIV-1 viremia prevents the establishment of interleukin 2-producing HIV-specific memory CD4+ T cells endowed with proliferative capacity. J Exp Med. 2003 Dec 15;198(12):1909-22. doi: 10.1084/jem.20031598.
- Background Lichterfeld M, Yu XG, Mui SK, Williams KL, Trocha A, Brockman MA, Allgaier RL, Waring MT, Koibuchi T, Johnston MN, Cohen D, Allen TM, Rosenberg ES, Walker BD, Altfeld M. Selective depletion of high-avidity human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T cells after early HIV-1 infection. J Virol. 2007 Apr;81(8):4199-214. doi: 10.1128/JVI.01388-06. Epub 2007 Feb 7.
- Background Zanussi S, Simonelli C, D'Andrea M, Caffau C, Clerici M, Tirelli U, DePaoli P. CD8+ lymphocyte phenotype and cytokine production in long-term non-progressor and in progressor patients with HIV-1 infection. Clin Exp Immunol. 1996 Aug;105(2):220-4. doi: 10.1046/j.1365-2249.1996.d01-746.x.
- Background Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, Boulassel MR, Delwart E, Sepulveda H, Balderas RS, Routy JP, Haddad EK, Sekaly RP. Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med. 2006 Oct;12(10):1198-202. doi: 10.1038/nm1482. Epub 2006 Aug 20.
- Background Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature. 2007 Sep 27;449(7161):419-26. doi: 10.1038/nature06175.
- Background Nicolette CA, Healey D, Tcherepanova I, Whelton P, Monesmith T, Coombs L, Finke LH, Whiteside T, Miesowicz F. Dendritic cells for active immunotherapy: optimizing design and manufacture in order to develop commercially and clinically viable products. Vaccine. 2007 Sep 27;25 Suppl 2:B47-60. doi: 10.1016/j.vaccine.2007.06.006. Epub 2007 Jun 21.
- Background Osada T, Clay TM, Woo CY, Morse MA, Lyerly HK. Dendritic cell-based immunotherapy. Int Rev Immunol. 2006 Sep-Dec;25(5-6):377-413. doi: 10.1080/08830180600992456.
- Background Connolly NC, Whiteside TL, Wilson C, Kondragunta V, Rinaldo CR, Riddler SA. Therapeutic immunization with human immunodeficiency virus type 1 (HIV-1) peptide-loaded dendritic cells is safe and induces immunogenicity in HIV-1-infected individuals. Clin Vaccine Immunol. 2008 Feb;15(2):284-92. doi: 10.1128/CVI.00221-07. Epub 2007 Oct 17.
- Background Garcia F, Lejeune M, Climent N, Gil C, Alcami J, Morente V, Alos L, Ruiz A, Setoain J, Fumero E, Castro P, Lopez A, Cruceta A, Piera C, Florence E, Pereira A, Libois A, Gonzalez N, Guila M, Caballero M, Lomena F, Joseph J, Miro JM, Pumarola T, Plana M, Gatell JM, Gallart T. Therapeutic immunization with dendritic cells loaded with heat-inactivated autologous HIV-1 in patients with chronic HIV-1 infection. J Infect Dis. 2005 May 15;191(10):1680-5. doi: 10.1086/429340. Epub 2005 Apr 11.
- Background Lu W, Arraes LC, Ferreira WT, Andrieu JM. Therapeutic dendritic-cell vaccine for chronic HIV-1 infection. Nat Med. 2004 Dec;10(12):1359-65. doi: 10.1038/nm1147. Epub 2004 Nov 28.
- Background Whiteside TL, Piazza P, Reiter A, Stanson J, Connolly NC, Rinaldo CR Jr, Riddler SA. Production of a dendritic cell-based vaccine containing inactivated autologous virus for therapy of patients with chronic human immunodeficiency virus type 1 infection. Clin Vaccine Immunol. 2009 Feb;16(2):233-40. doi: 10.1128/CVI.00066-08. Epub 2008 Nov 26.
- Background Ide F, Nakamura T, Tomizawa M, Kawana-Tachikawa A, Odawara T, Hosoya N, Iwamoto A. Peptide-loaded dendritic-cell vaccination followed by treatment interruption for chronic HIV-1 infection: a phase 1 trial. J Med Virol. 2006 Jun;78(6):711-8. doi: 10.1002/jmv.20612.
- Background Maldarelli F, Palmer S, King MS, Wiegand A, Polis MA, Mican J, Kovacs JA, Davey RT, Rock-Kress D, Dewar R, Liu S, Metcalf JA, Rehm C, Brun SC, Hanna GJ, Kempf DJ, Coffin JM, Mellors JW. ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathog. 2007 Apr;3(4):e46. doi: 10.1371/journal.ppat.0030046.
- Background Palmer S, Maldarelli F, Wiegand A, Bernstein B, Hanna GJ, Brun SC, Kempf DJ, Mellors JW, Coffin JM, King MS. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3879-84. doi: 10.1073/pnas.0800050105. Epub 2008 Mar 10.
- Background Archin NM, Liberty AL, Kashuba AD, Choudhary SK, Kuruc JD, Crooks AM, Parker DC, Anderson EM, Kearney MF, Strain MC, Richman DD, Hudgens MG, Bosch RJ, Coffin JM, Eron JJ, Hazuda DJ, Margolis DM. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012 Jul 25;487(7408):482-5. doi: 10.1038/nature11286.
- Background Shan L, Deng K, Shroff NS, Durand CM, Rabi SA, Yang HC, Zhang H, Margolick JB, Blankson JN, Siliciano RF. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation. Immunity. 2012 Mar 23;36(3):491-501. doi: 10.1016/j.immuni.2012.01.014. Epub 2012 Mar 8.
- Background DeBenedette MA, Calderhead DM, Ketteringham H, Gamble AH, Horvatinovich JM, Tcherepanova IY, Nicolette CA, Healey DG. Priming of a novel subset of CD28+ rapidly expanding high-avidity effector memory CTL by post maturation electroporation-CD40L dendritic cells is IL-12 dependent. J Immunol. 2008 Oct 15;181(8):5296-305. doi: 10.4049/jimmunol.181.8.5296.
- Background Calderhead DM, DeBenedette MA, Ketteringham H, Gamble AH, Horvatinovich JM, Tcherepanova IY, Nicolette CA, Healey DG. Cytokine maturation followed by CD40L mRNA electroporation results in a clinically relevant dendritic cell product capable of inducing a potent proinflammatory CTL response. J Immunother. 2008 Oct;31(8):731-41. doi: 10.1097/CJI.0b013e318183db02.
- Background Tcherepanova I, Harris J, Starr A, Cleveland J, Ketteringham H, Calderhead D, Horvatinovich J, Healey D, Nicolette CA. Multiplex RT-PCR amplification of HIV genes to create a completely autologous DC-based immunotherapy for the treatment of HIV infection. PLoS One. 2008 Jan 30;3(1):e1489. doi: 10.1371/journal.pone.0001489.
- Background Addo MM, Yu XG, Rosenberg ES, Walker BD, Altfeld M. Cytotoxic T-lymphocyte (CTL) responses directed against regulatory and accessory proteins in HIV-1 infection. DNA Cell Biol. 2002 Sep;21(9):671-8. doi: 10.1089/104454902760330219.
- Background Van Gulck ER, Ponsaerts P, Heyndrickx L, Vereecken K, Moerman F, De Roo A, Colebunders R, Van den Bosch G, Van Bockstaele DR, Van Tendeloo VF, Allard S, Verrier B, Maranon C, Hoeffel G, Hosmalin A, Berneman ZN, Vanham G. Efficient stimulation of HIV-1-specific T cells using dendritic cells electroporated with mRNA encoding autologous HIV-1 Gag and Env proteins. Blood. 2006 Mar 1;107(5):1818-27. doi: 10.1182/blood-2005-01-0339. Epub 2005 Nov 1.
- Background Altfeld M, Addo MM, Eldridge RL, Yu XG, Thomas S, Khatri A, Strick D, Phillips MN, Cohen GB, Islam SA, Kalams SA, Brander C, Goulder PJ, Rosenberg ES, Walker BD; HIV Study Collaboration. Vpr is preferentially targeted by CTL during HIV-1 infection. J Immunol. 2001 Sep 1;167(5):2743-52. doi: 10.4049/jimmunol.167.5.2743.
- Background Novitsky V, Cao H, Rybak N, Gilbert P, McLane MF, Gaolekwe S, Peter T, Thior I, Ndung'u T, Marlink R, Lee TH, Essex M. Magnitude and frequency of cytotoxic T-lymphocyte responses: identification of immunodominant regions of human immunodeficiency virus type 1 subtype C. J Virol. 2002 Oct;76(20):10155-68. doi: 10.1128/jvi.76.20.10155-10168.2002.
- Background Quaranta MG, Mattioli B, Giordani L, Viora M. The immunoregulatory effects of HIV-1 Nef on dendritic cells and the pathogenesis of AIDS. FASEB J. 2006 Nov;20(13):2198-208. doi: 10.1096/fj.06-6260rev.
- Background Majumder B, Janket ML, Schafer EA, Schaubert K, Huang XL, Kan-Mitchell J, Rinaldo CR Jr, Ayyavoo V. Human immunodeficiency virus type 1 Vpr impairs dendritic cell maturation and T-cell activation: implications for viral immune escape. J Virol. 2005 Jul;79(13):7990-8003. doi: 10.1128/JVI.79.13.7990-8003.2005.
- Background Tcherepanova I, Starr A, Lackford B, Adams MD, Routy JP, Boulassel MR, Calderhead D, Healey D, Nicolette C. The immunosuppressive properties of the HIV Vpr protein are linked to a single highly conserved residue, R90. PLoS One. 2009 Jun 10;4(6):e5853. doi: 10.1371/journal.pone.0005853.
- Background Morse MA, Coleman RE, Akabani G, Niehaus N, Coleman D, Lyerly HK. Migration of human dendritic cells after injection in patients with metastatic malignancies. Cancer Res. 1999 Jan 1;59(1):56-8.
- Background Serody JS, Collins EJ, Tisch RM, Kuhns JJ, Frelinger JA. T cell activity after dendritic cell vaccination is dependent on both the type of antigen and the mode of delivery. J Immunol. 2000 May 1;164(9):4961-7. doi: 10.4049/jimmunol.164.9.4961.
- Background Routy JP, Boulassel MR, Yassine-Diab B, Nicolette C, Healey D, Jain R, Landry C, Yegorov O, Tcherepanova I, Monesmith T, Finke L, Sekaly RP. 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. doi: 10.1016/j.clim.2009.09.009. Epub 2009 Nov 4.
- Background Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA, Walker BD. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science. 1997 Nov 21;278(5342):1447-50. doi: 10.1126/science.278.5342.1447.
- Background Rosenberg ES, Altfeld M, Poon SH, Phillips MN, Wilkes BM, Eldridge RL, Robbins GK, D'Aquila RT, Goulder PJ, Walker BD. Immune control of HIV-1 after early treatment of acute infection. Nature. 2000 Sep 28;407(6803):523-6. doi: 10.1038/35035103.
- Background Volberding P, Demeter L, Bosch RJ, Aga E, Pettinelli C, Hirsch M, Vogler M, Martinez A, Little S, Connick E; ACTG 371 Team. Antiretroviral therapy in acute and recent HIV infection: a prospective multicenter stratified trial of intentionally interrupted treatment. AIDS. 2009 Sep 24;23(15):1987-95. doi: 10.1097/QAD.0b013e32832eb285.
- Background Hecht FM, Wang L, Collier A, Little S, Markowitz M, Margolick J, Kilby JM, Daar E, Conway B, Holte S; AIEDRP Network. A multicenter observational study of the potential benefits of initiating combination antiretroviral therapy during acute HIV infection. J Infect Dis. 2006 Sep 15;194(6):725-33. doi: 10.1086/506616. Epub 2006 Aug 15.
- Background Ortiz GM, Nixon DF, Trkola A, Binley J, Jin X, Bonhoeffer S, Kuebler PJ, Donahoe SM, Demoitie MA, Kakimoto WM, Ketas T, Clas B, Heymann JJ, Zhang L, Cao Y, Hurley A, Moore JP, Ho DD, Markowitz M. HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. J Clin Invest. 1999 Sep;104(6):R13-8. doi: 10.1172/JCI7371.
- Background Bongiovanni M, Casana M, Tincati C, d'Arminio Monforte A. Treatment interruptions in HIV-infected subjects. J Antimicrob Chemother. 2006 Sep;58(3):502-5. doi: 10.1093/jac/dkl268. Epub 2006 Jul 1.
- Background Rosenberg ZF, Fauci AS. Immunopathogenic mechanisms of HIV infection: cytokine induction of HIV expression. Immunol Today. 1990 May;11(5):176-80. doi: 10.1016/0167-5699(90)90070-p.
- Background Pilcher CD, Eron JJ Jr, Galvin S, Gay C, Cohen MS. Acute HIV revisited: new opportunities for treatment and prevention. J Clin Invest. 2004 Apr;113(7):937-45. doi: 10.1172/JCI21540.
- Background Pires A, Hardy G, Gazzard B, Gotch F, Imami N. Initiation of antiretroviral therapy during recent HIV-1 infection results in lower residual viral reservoirs. J Acquir Immune Defic Syndr. 2004 Jul 1;36(3):783-90. doi: 10.1097/00126334-200407010-00004.
- Background Ramratnam B, Ribeiro R, He T, Chung C, Simon V, Vanderhoeven J, Hurley A, Zhang L, Perelson AS, Ho DD, Markowitz M. Intensification of antiretroviral therapy accelerates the decay of the HIV-1 latent reservoir and decreases, but does not eliminate, ongoing virus replication. J Acquir Immune Defic Syndr. 2004 Jan 1;35(1):33-7. doi: 10.1097/00126334-200401010-00004.
- Background Chamberland A, Sylla M, Boulassel MR, Baril JG, Cote P, Thomas R, Trottier B, Rouleau D, Routy JP, Tremblay C; Investigators of the Primary HIV-Infection Cohort of Montreal. Effect of antiretroviral therapy on HIV-1 genetic evolution during acute infection. Int J STD AIDS. 2011 Mar;22(3):146-50. doi: 10.1258/ijsa.2010.010292.
- Background Keedy KS, Archin NM, Gates AT, Espeseth A, Hazuda DJ, Margolis DM. A limited group of class I histone deacetylases acts to repress human immunodeficiency virus type 1 expression. J Virol. 2009 May;83(10):4749-56. doi: 10.1128/JVI.02585-08. Epub 2009 Mar 11.
- Background Yukl SA, Boritz E, Busch M, Bentsen C, Chun TW, Douek D, Eisele E, Haase A, Ho YC, Hutter G, Justement JS, Keating S, Lee TH, Li P, Murray D, Palmer S, Pilcher C, Pillai S, Price RW, Rothenberger M, Schacker T, Siliciano J, Siliciano R, Sinclair E, Strain M, Wong J, Richman D, Deeks SG. Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient. PLoS Pathog. 2013;9(5):e1003347. doi: 10.1371/journal.ppat.1003347. Epub 2013 May 9.
- Background Azzoni L, Foulkes AS, Papasavvas E, Mexas AM, Lynn KM, Mounzer K, Tebas P, Jacobson JM, Frank I, Busch MP, Deeks SG, Carrington M, O'Doherty U, Kostman J, Montaner LJ. Pegylated Interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration. J Infect Dis. 2013 Jan 15;207(2):213-22. doi: 10.1093/infdis/jis663. Epub 2012 Oct 26.
- Background Liszewski MK, Yu JJ, O'Doherty U. Detecting HIV-1 integration by repetitive-sampling Alu-gag PCR. Methods. 2009 Apr;47(4):254-60. doi: 10.1016/j.ymeth.2009.01.002. Epub 2009 Feb 3.
- Background Palmer S, Wiegand AP, Maldarelli F, Bazmi H, Mican JM, Polis M, Dewar RL, Planta A, Liu S, Metcalf JA, Mellors JW, Coffin JM. New real-time reverse transcriptase-initiated PCR assay with single-copy sensitivity for human immunodeficiency virus type 1 RNA in plasma. J Clin Microbiol. 2003 Oct;41(10):4531-6. doi: 10.1128/JCM.41.10.4531-4536.2003.
- Background Archin NM, Eron JJ, Palmer S, Hartmann-Duff A, Martinson JA, Wiegand A, Bandarenko N, Schmitz JL, Bosch RJ, Landay AL, Coffin JM, Margolis DM. Valproic acid without intensified antiviral therapy has limited impact on persistent HIV infection of resting CD4+ T cells. AIDS. 2008 Jun 19;22(10):1131-5. doi: 10.1097/QAD.0b013e3282fd6df4.
- Background Gandhi RT, Zheng L, Bosch RJ, Chan ES, Margolis DM, Read S, Kallungal B, Palmer S, Medvik K, Lederman MM, Alatrakchi N, Jacobson JM, Wiegand A, Kearney M, Coffin JM, Mellors JW, Eron JJ; AIDS Clinical Trials Group A5244 team. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLoS Med. 2010 Aug 10;7(8):e1000321. doi: 10.1371/journal.pmed.1000321.
- Background Tcherepanova, I, Harri, J, Horvatinovich, J, et al. Autologous dendritic cell based therapy modulates proviral DNA levels in chronically HIV-infected subjects. AIDS Vaccine 2013 7 - 10 October in Barcelona, Spain.
- Background Wolf J, Bogner C, Hoffmann V, Avettand-Fenoel K, Schewe R, Pauli J, et al. 5-drug HAART during primary HIV infection leads to a reduction of proviral DNA levels in comparison to levels achievable during chronic infection. In: 7th IAS Conference on HIV Pathogenesis. Kuala Lumpur, Malaysia; 2013.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | AGS-004 | Cell therapy | 1.2e+07 cells | Other |