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.

Fig. 1.

No virological response to PD-1 blockade in long-term persistent HCV infection with poor intrahepatic T-cell responses. (A) Dosing regimen for anti–PD-1 antibodies in Ch1535. (B) Serum levels of HCV RNA and ALT were measured in Ch1535 at the indicated time points. Baseline viremia is presented as the mean (± 1 SD) of HCV RNA at six time points over a 12-mo period before initiation of anti–PD-1 therapy. (C) Levels of anti–PD-1 antibodies in serum were measured by a quantitative antigen capture ELISA. Samples were collected immediately before each dose of anti–PD-1 was administered. Vertical dashed lines in B and C represent time points at which anti–PD-1 antibodies were administered. (D) Magnitude of in vitro–expanded CD4+ (white bars) and CD8+ (black bars) intrahepatic T-cell responses to HCV genotype-matched peptide pools are indicated at various time points. (E) Relative distribution of the intrahepatic CD4+ and CD8+ T-cell responses to each of nine separate pools of genotype-matched HCV peptide pools is depicted to show the breadth of the response to HCV; ND, not detected.

Fig. 2.

PD-1 blockade fails to alter viral load in short-term persistent HCV infection with poor intrahepatic T-cell responses. (A) Dosing regimen for anti–PD-1 antibodies in Ch5276. (B) Serum levels of HCV RNA and ALT were measured in Ch5276 at the indicated time points. Baseline viremia is presented as the mean (± 1 SD) of HCV RNA levels over a 4-mo period before initiation of anti–PD-1 therapy. (C) Levels of anti–PD-1 antibodies in serum measured immediately before each dose of anti–PD-1 was administered. Vertical dashed lines in B and C represent time points at which anti–PD-1 antibodies were administered. (D) Magnitude of in vitro–expanded CD4+ (white bars) and CD8+ (black bars) intrahepatic T-cell responses to HCV genotype-matched peptide pools are indicated at various time points. (E) Relative distribution of the intrahepatic CD4+ and CD8+ T-cell responses to each of nine separate pools of genotype-matched HCV peptide pools is depicted to show the breadth of the response to HCV.

Fig. 3.

Transient decline of viral load associated with anti–PD-1 treatment in short-term persistent HCV infection with broad intrahepatic T-cell responses. (A) Dosing regimen for anti–PD-1 antibodies in Ch5300. (B) Serum levels of HCV RNA and ALT were measured in Ch5300 at the indicated time points. Baseline viremia is presented as the mean (± 1 SD) of HCV RNA measured over a 4-mo period before initiation of anti–PD-1 therapy. (C) Pharmacokinetic of anti–PD-1 antibodies in serum measured immediately before each dose of anti–PD-1 was administered. Vertical dashed lines in B and C represent time points at which anti–PD-1 antibodies were administered. (D) Magnitude of in vitro–expanded CD4+ (white bars) and CD8+ (black bars) intrahepatic T-cell responses to HCV genotype-matched peptide pools are indicated at various time points. (E) Relative distribution of the intrahepatic CD4+ and CD8+ T-cell responses to each of nine separate pools of genotype-matched HCV peptide pools is depicted to show the breadth of the response to HCV. (F) Combined IFN-γ ELIspot responses to the nine HCV peptide pools by peripheral blood mononuclear cells are shown for study days 0 and 21.