HIV-1 infected persons with viremia suppressed on antiretroviral therapy (ART) have persistent T-cell exhaustion that may limit clearance of HIV-1 expressing cells. Monoclonal antibodies (mAbs) targeting the PD1:PD-L1 axis have shown clinical activity in cancer studies. Blocking this axis in patients suppressed on ART may improve HIV-1 specific immune responses.
In a pre-specified analysis of an initial dosing cohort of ACTG 5326, 8 HIV-infected participants on ART with HIV-1 RNA <40 c/mL and ≥0.4 c/mL by single copy assay (SCA) received one infusion (double-blind) of anti PD-L1 mAb (BMS-936559) at 0.3 mg/kg (N = 6) or normal saline (NS) (N=2). Anti-PD-L1 pharmacokinetics and receptor occupancy (RO) on CD3+, CD4+ and CD8+ T cells were measured and safety was assessed. HIV-1 Gag-specific CD8+ T cell responses, plasma HIV-1 RNA by SCA, and CD4+ T cell-associated (CA) RNA and DNA by qPCR were measured at pre-entry, entry and over 28 days post infusion. In participants who received active mAb, pre-entry/entry (BL) and all post-infusion values were averaged and compared (paired t-test).
BMS-936559 was well tolerated; all treatment-related adverse events were mild/moderate. Plasma half-life of BMS-936559 was 3.7 days. RO peaked at 80-100% within 2 hours of dosing and was <20% in 5 of 6 participants by week 4. The average percentage of HIV-1 Gag-specific CD8+ cells (by IFNg (Figure) or CD107a) increased over the 28 days post infusion (p=0.14 and 0.09, respectively), as did polyfunctionality of the Gag-specific CD8+ T cell response, all driven by two strong responders in the anti-PD-L1 treated group. SCA levels appeared to decrease at 3d then increase at 7d (Figure). There was no change in the average SCA HIV RNA or CA-HIV RNA from pre-infusion through Day 28 (p=0.69 and 0.53). CA-RNA:DNA ratio did not change. At 36 weeks post-infusion of anti-PD-L1 mAb or NS, an asymptomatic participant with a previously normal cortisol had an abnormally low AM level and was diagnosed with pituitary insufficiency.
This is the first prospective study of a PD1:PD-L1 axis inhibitor in HIV-infected participants on ART. Despite the low anti PD-L1 dose, there was a trend toward increased HIV-1 Gag specific CD8+ T cell responses over 28 days post-infusion, including increased CD107a expression consistent with reversal of CD8+ T cell exhaustion. Responses were larger in a subset, consistent with responses to immune checkpoint mAbs in cancer treatment and animal models of viral infections.