Abstract
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.Trial RegistrationClinicalTrials.gov NCT00703469 NCT00703469
Highlights
Virus-induced suppression of host immunity contributes to the persistence of chronic infections with clinically important viruses including hepatitis C virus (HCV), hepatitis B virus (HBV), and human immunodeficiency virus (HIV) [1,2,3]
While T cells play a critical role in viral clearance, chronic immune activation resulting from prolonged antigen expression can trigger T cell exhaustion and dysfunction, further contributing to viral persistence [1,9,10,12]
At the highest administered dose (10 mg/kg), HCV RNA reductions .4 log10 IU/mL were observed in three patients
Summary
Virus-induced suppression of host immunity contributes to the persistence of chronic infections with clinically important viruses including hepatitis C virus (HCV), hepatitis B virus (HBV), and human immunodeficiency virus (HIV) [1,2,3]. Various immunomodulators have been evaluated as therapeutics for these infections, with the goal of overcoming and/or reversing virusinduced immunosuppression These include interferon-alfa, which is well-established in therapy of HBV and HCV infections, as well as interferon-lambda, toll-like receptor 7 agonists, interleukin-2, interleukin-7, therapeutic vaccines, and other agents [1,4,5,6,7,8]. While T cells play a critical role in viral clearance, chronic immune activation resulting from prolonged antigen expression can trigger T cell exhaustion and dysfunction, further contributing to viral persistence [1,9,10,12]. Analysis of T cells in the lymphocytic choriomeningitis virus (LCMV) mouse model of chronic viral infection has demonstrated that the exhausted T cell phenotype is driven, at least in part, by the expression and function of the inhibitory receptor, programmed death 1 (PD-1) [13]
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