Clinical Trial of the Anti-PD-L1 Antibody BMS-936559 in HIV-1 Infected Participants on Suppressive Antiretroviral Therapy

Abstract

Background: Reversing immune exhaustion with an anti-PD-L1 antibody may improve human immunodeficiency virus type 1 (HIV-1)-specific immunity and increase clearance of HIV-1-expressing cells.

Methods: We conducted a phase I, randomized, double-blind, placebo-controlled, dose-escalating study of BMS-936559, including HIV-1-infected adults aged >18 to <70 years on suppressive antiretroviral therapy with CD4+ counts >350 cells/μL and detectable plasma HIV-1 RNA by single-copy assay. Data on single infusions of BMS-936559 (0.3 mg/kg) versus placebo are described. The primary outcomes were safety defined as any grade 3 or greater or immune-related adverse event (AE) and the change in HIV-1 Gag-specific CD8+ T cell responses from baseline to day 28 after infusion.

Results: Eight men enrolled: 6 received 0.3 mg/kg of BMS-936559, and 2 received placebo infusions. There were no BMS-936559-related grade 3 or greater AEs. In 1 participant, asymptomatic hypophysitis (a protocol-defined immune-related AE) was identified 266 days after BMS-936559 infusion; it resolved over time. The mean percentage of HIV-1 Gag-specific CD8+ T cells expressing interferon γ increased from baseline (0.09%) through day 28 (0.20%; P = .14), driven by substantial increases in 2 participants who received BMS-936559.

Conclusions: In this first evaluation of an immunologic checkpoint inhibitor in healthy HIV-1-infected persons, single low-dose BMS-936559 infusions appeared to enhance HIV-1-specific immunity in a subset of participants.

Clinical trials registration: NCT02028403.

Keywords: BMS-936559; HIV cure; HIV eradication; anti-PD-L1; checkpoint inhibitors; human immunodeficiency virus type 1 (HIV-1); immune response.

© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Change from baseline over time in the absolute percentage of human immunodeficiency virus type 1 (HIV-1) Gag-specific CD8+ T cells. Gag-specific CD8+ T cell responses from baseline (average of pre-entry and entry) through week 48 are shown for interferon γ (IFN-γ) (A), CD107a (B), and tumor necrosis factor (TNF) (C). In each panel, the upper 2 graphs show the change in the percentage of HIV Gag-specific responses over 48 weeks of the study. The lower 2 graphs in highlight the first 28 days of the study, which defined the primary immunologic endpoint. Two participants who received treatment with BMS-936559 and appeared to show an increase in HIV-1 Gag-specific CD8+ responses are shown as green lines. The black line with circular markers represents the mean change over time. A, Change in HIV-1 Gag-specific CD8+ T cells by intracellular cytokine staining for IFN-γ. B, Change in HIV-1 Gag-specific CD8+ T cells by mobilization of CD107a. C, Change in HIV-1 Gag-specific CD8+ T cells by mobilization of TNF. Abbreviations: BL, baseline; HIV-1, human immunodeficiency virus type 1; IFN-γ, interferon γ; TNF, tumor necrosis factor.

Figure 2.

Correlation between pre-entry ex vivo proliferation to Gag and in vivo Gag-specific CD8+ T-cell responses in each participant. The predefined primary endpoint for in vivo response was the change in magnitude of human immunodeficiency virus type 1 (HIV-1) Gag-specific CD8+ T cells by intracellular staining for interferon γ from baseline to 28 days after treatment (the average of day 7, 14, and 28 measurements). Shown are the average differences in pretreatment ex vivo proliferative responses to Gag peptides after BMS-936559 exposure compared with isotype control versus the average difference in pre- and post-treatment in vivo HIV-1 Gag-specific CD8+ responses for each of the 3 measures of response. Results from the 2 participants with apparent in vivo responses are shown in green. Abbreviations: IFN-γ, interferon γ; TNF, tumor necrosis factor.

Figure 3.

Change from baseline over time in the absolute percentage of human immunodeficiency virus type 1 Gag-specific CD8+ T cells that were poly-functional defined by cells staining for interferon γ, CD107a mobilization, and tumor necrosis factor from baseline through week 48. Abbreviations: BL, baseline; HIV-1, human immunodeficiency virus type 1; IFN-γ, interferon γ; TNF, tumor necrosis factor.