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Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1).

ABSTRACT: Hepatitis C virus (HCV) persistence is facilitated by exhaustion of CD8+ T cells that express the inhibitory receptor programmed cell death 1 (PD-1). Blockade of PD-1 signaling improves in vitro proliferation of HCV-specific T lymphocytes, but whether antiviral function can be restored in infected individuals is unknown. To address this question, chimpanzees with persistent HCV infection were treated with anti-PD-1 antibodies. A significant reduction in HCV viremia was observed in one of three treated animals without apparent hepatocellular injury. Viremia rebounded in the responder animal when antibody treatment was discontinued. Control of HCV replication was associated with restoration of intrahepatic CD4+ and CD8+ T-cell immunity against multiple HCV proteins. The responder animal had a history of broader T-cell immunity to multiple HCV proteins than the two chimpanzees that did not respond to PD-1 therapy. The results suggest that successful PD-1 blockade likely requires a critical threshold of preexisting virus-specific T cells in liver and warrants consideration of therapeutic vaccination strategies in combination with PD-1 blockade to broaden narrow responses. Anti-PD-1 immunotherapy may also facilitate control of other persistent viruses, notably the hepatitis B virus where options for long-term control of virus replication are limited.

SUBMITTER: Fuller MJ

PROVIDER: S-EPMC3773803 | biostudies-other | 2013 Sep

REPOSITORIES: biostudies-other

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Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1).

Fuller Michael J MJ Callendret Benoit B Zhu Baogong B Freeman Gordon J GJ Hasselschwert Dana L DL Satterfield William W Sharpe Arlene H AH Dustin Lynn B LB Rice Charles M CM Grakoui Arash A Ahmed Rafi R Walker Christopher M CM

Proceedings of the National Academy of Sciences of the United States of America 20130826 37

Hepatitis C virus (HCV) persistence is facilitated by exhaustion of CD8+ T cells that express the inhibitory receptor programmed cell death 1 (PD-1). Blockade of PD-1 signaling improves in vitro proliferation of HCV-specific T lymphocytes, but whether antiviral function can be restored in infected individuals is unknown. To address this question, chimpanzees with persistent HCV infection were treated with anti-PD-1 antibodies. A significant reduction in HCV viremia was observed in one of three t ...[more]

PMID: 23980172

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Project description:Expression of the programmed death 1 (PD-1) receptor and its ligands are implicated in the T cell exhaustion phenotype which contributes to the persistence of several chronic viral infections, including human hepatitis C virus (HCV). The antiviral potential of BMS-936558 (MDX-1106) - a fully human anti-PD-1 monoclonal immunoglobulin-G4 that blocks ligand binding - was explored in a proof-of-concept, placebo-controlled single-ascending-dose study in patients (N?=?54) with chronic HCV infection. Interferon-alfa treatment-experienced patients (n?=?42) were randomized 5?1 to receive a single infusion of BMS-936558 (0.03, 0.1, 0.3, 1.0, 3.0 mg/kg [n?=?5 each] or 10 mg/kg [n?=?10]) or of placebo (n?=?7). An additional 12 HCV treatment-naïve patients were randomized to receive 10 mg/kg BMS-936558 (n?=?10) or placebo (n?=?2). Patients were followed for 85 days post-dose. Five patients who received BMS-936558 (0.1 [n?=?1] or 10 mg/kg) and one placebo patient achieved the primary study endpoint of a reduction in HCV RNA ?0.5 log10 IU/mL on at least 2 consecutive visits; 3 (10 mg/kg) achieved a >4 log10 reduction. Two patients (10 mg/kg) achieved HCV RNA below the lower limit of quantitation (25 IU/mL), one of whom (a prior null-responder) remained RNA-undetectable 1 year post-study. Transient reductions in CD4(+), CD8(+) and CD19(+) cells, including both naïve and memory CD4(+) and CD8(+) subsets, were observed at Day 2 without evidence of immune deficit. No clinically relevant changes in immunoglobulin subsets or treatment-related trends in circulating cytokines were noted. BMS-936558 exhibited dose-related exposure increases, with a half-life of 20-24 days. BMS-936558 was mostly well tolerated. One patient (10 mg/kg) experienced an asymptomatic grade 4 ALT elevation coincident with the onset of a 4-log viral load reduction. Six patients exhibited immune-related adverse events of mild-to-moderate intensity, including two cases of hyperthyroidism consistent with autoimmune thyroiditis. Further investigation of PD-1 pathway blockade in chronic viral disease is warranted.ClinicalTrials.gov NCT00703469.

Dataset Information

Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1).

Publications

Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1).

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