Immunogenicity of AGS-004 Dendritic Cell Therapy in Patients Treated During Acute HIV Infection
Cynthia L Gay, Mark A DeBenedette, Irina Y Tcherepanova, Alicia Gamble, Whitney E Lewis, Anna B Cope, JoAnn D Kuruc, Kara S McGee, Mary F Kearney, John M Coffin, Nancie M Archin, Charles B Hicks, Joseph J Eron, Charles A Nicolette, David M Margolis, Cynthia L Gay, Mark A DeBenedette, Irina Y Tcherepanova, Alicia Gamble, Whitney E Lewis, Anna B Cope, JoAnn D Kuruc, Kara S McGee, Mary F Kearney, John M Coffin, Nancie M Archin, Charles B Hicks, Joseph J Eron, Charles A Nicolette, David M Margolis
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.
Keywords: HIV; HIV eradication; acute HIV infection; analytic treatment interruption; dendritic cell vaccine.
Conflict of interest statement
C.G. has received research support from Bristol Myers Squibb, Gilead Sciences, Abbott, and Janssen (formerly Tibotec Therapeutics). C.H. has received grant support and/or consulting/honoraria from BMS, GSK, Merck, Tibotec Therapeutics, Gilead, Myriad Pharmaceuticals, and Pfizer. D.M. has received research support from Bristol Myers Squibb, Gilead Sciences, and Janssen, has consulted for Merck, and holds common stock in Gilead Sciences. J.E. receives research support from ViiV Healthcare and is a consultant to Bristol Myers Squibb, Merck, Gilead, Janssen, and ViiV Healthcare. M.D., I.T., E.V., A.G., W.L., and C.N. are employees of Argos Therapeutics, Inc., and M.D., E.V., I.T., and C.N have been granted stock options in the company. A.C., J.K., K.M., and M.M. have no competing financial interests.
Funding Sources: This project has been funded in whole or in part by Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under contract no. N01-AI-60019, AI50410 to the UNC CFAR, and in part by NIH U19-AI096113 to D.M.M. Single-copy assays were funded by intramural NIH funding.
Prior presentation of interim data by: Gay C, Archin N, Tcherepanova I, Villiard E, Hicks C, Kearney M, Coffin J, DeBenedette, M, Eron J, Nicolette C, Margolis DM. Immunogenicity of AGS-004 Dendritic Cell Therapy in Patients Treated during Acute HIV Infection. 21st Conference on Retroviruses and Opportunistic Infections 2014, Boston, MA. March 2–6, Abstract 344.
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Source: PubMed