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.

Interferon-γ-induced activation of JAK1 and JAK2 suppresses tumor cell susceptibility to NK cells through upregulation of PD-L1 expression

“…For PD-L1 blocking experiments, we used a humanized anti-PD-L1 mAb with human IgG4 to eliminate FcR-mediated effects and S228P mutated to allow efficient dimerization (clone 29F.2A3). 45,51 NK-92 or primary NK cells were incubated with cell lines or primary cells with or without 10 mg/mL anti-PD-L1 mAb for 12 h. 40 nM of JAK inhibitor 1 was also added to the culture and the level of killing was detected using AnnexinV-FITC/7AAD as described above. In some experiments, target cells were pre-treated with 10 Units/mL IFNg and subsequently incubated with primary purified NK cells with or without anti-PD-L1 mAb.…”

Modeling how reversal of immune exhaustion elicits cure of chronic hepatitis C after the end of treatment with direct‐acting antiviral agents

“…When the percentage of hepatocytes infected was reduced below a threshold, exhausted CTLs regained their functionality in a mouse model of HCV infection 31. Anti‐PD‐1 therapy, which prevents or reverses CTL exhaustion, has shown some success in HCV‐infected primates and humans 32, 33. Unlike the virologic hypothesis, however, whether the immunologic hypothesis is consistent with patient data of viral load changes during DAA treatments is unknown.…”

Immune outcomes in the liver: Is CD8 T cell fate determined by the environment?

“…One approach has been to block the signalling pathways leading to exhaustion. Blockade of inhibitory cytokines and co-inhibitory receptors individually or in combination have been tested in vivo using animal models [79][80][81]102] or in vitro using T cells from chronically infected patients [103][104][105][106][107]. The success of these strategies has been highly variable and is largely dependent on the phenotype of the exhausted T cells, including the expression of individual co-inhibitory receptors and the degree of the T cell exhaustion [107][108][109].…”

“…The success of these strategies has been highly variable and is largely dependent on the phenotype of the exhausted T cells, including the expression of individual co-inhibitory receptors and the degree of the T cell exhaustion [107][108][109]. In vivo experiments involving PD-1 blockade during simian immunodeficiency virus infection in macaques improved virus-specific T cell immunity [110], although results in chimpanzees and humans with chronic HCV infection have not associated with consistent effects on levels of viremia [102,111]. Another strategy has been to provide stimulatory molecules such as IL-12, an inflammatory cytokine important for T cell activation.…”