Safety and Immune Responses Following Anti-PD-1 Monoclonal Antibody Infusions in Healthy Persons With Human Immunodeficiency Virus on Antiretroviral Therapy

Abstract

Background: T cells in people with human immunodeficiency virus (HIV) demonstrate an exhausted phenotype, and HIV-specific CD4⁺ T cells expressing programmed cell death 1 (PD-1) are enriched for latent HIV, making antibody to PD-1 a potential strategy to target the latent reservoir.

Methods: This was a phase 1/2, randomized (4:1), double-blind, placebo-controlled study in adults with suppressed HIV on antiretroviral therapy with CD4⁺ counts ≥350 cells/μL who received 2 infusions of cemiplimab versus placebo. The primary outcome was safety, defined as any grade 3 or higher adverse event (AE) or any immune-related AE (irAE). Changes in HIV-1-specific polyfunctional CD4⁺ and CD8⁺ T-cell responses were evaluated.

Results: Five men were enrolled (median CD4⁺ count, 911 cells/μL; median age, 51 years); 2 received 1 dose of cemiplimab, 2 received 2 doses, and 1 received placebo. One participant had a probable irAE (thyroiditis, grade 2); another had a possible irAE (hepatitis, grade 3), both after a single low-dose (0.3 mg/kg) infusion. The Safety Monitoring Committee recommended no further enrollment or infusions. All 4 cemiplimab recipients were followed for 48 weeks. No other cemiplimab-related serious AEs, irAEs, or grade 3 or higher AEs occurred. One 2-dose recipient of cemiplimab had a 6.2-fold increase in polyfunctional, Gag-specific CD8⁺ T-cell frequency with supportive increases in plasma HIV RNA and decreases in total HIV DNA.

Conclusions: One of 4 participants exhibited increased HIV-1-specific T-cell responses and transiently increased HIV-1 expression following 2 cemiplimab infusions. The occurrence of irAEs after a single, low dose may limit translating the promising therapeutic results of cemiplimab for cancer to immunotherapeutic and latency reversal strategies for HIV. Clinical Trials Registration. NCT03787095.

Keywords: HIV; HIV cure; HIV latency; anti-PD-1 inhibitor; immune checkpoint inhibitors.

Figure 1.

Antithyroglobulin antibodies (A) and thyroperoxidase antibodies (B) over time for each participant. Participant (Pt) #1 and Pt #2 received 2 doses of cemiplimab. Pt #3 and #4 received a single dose of cemiplimab due to suspected adverse events. Pt #5 received 1 placebo dose. Pt #3 (shown in blue, thyroiditis immune-related adverse event [AE]) had a detectable pretreatment antithyroglobulin antibody level and thyroperoxidase antibody level with an increase in both measures after cemiplimab infusion. Alanine aminotransferase (ALT; C) and aspartate aminotransferase (AST; D) over time for each participant. Pt #4 (shown in green, liver injury AE) experienced increased AST and ALT at week 2. Elevated AST and ALT (grade 1–2) recurred for this participant at weeks 20, 29, and 48, attributed to ongoing alcohol use.

Figure 2.

Hysteresis plot of cemiplimab receptor occupancy (RO) on CD3⁺ T cells relative to cemiplimab concentrations in serum in people with human immunodeficiency virus after a single intravenous (IV) dose of cemiplimab 0.3 mg/kg IV. Cemiplimab RO on CD3⁺ T cells at low cemiplimab concentrations are shown for the 2 participants (Pt #3 and #4) who received only a single cemiplimab infusion to demonstrate persistent receptor occupancy at the lowest cemiplimab concentration levels.

Figure 3.

Programmed cell death 1 (PD-1) expression on CD4⁺ and CD8⁺ T cells over time for each participant. All participants had decreased frequency of PD-1⁺ T cells after the first cemiplimab infusion. Participant (Pt) #1 (shown in red, immune responder) had the highest pretreatment PD-1 expression percentage on CD4⁺ T cells. Pt #3 and #4 received a single dose of cemiplimab; Pts #1 and #2 received 2 doses of cemiplimab. Abbreviations: AE, adverse event; PD-1, programmed cell death 1.

Figure 4.

Programmed cell death 1 receptor occupancy expression over time for each participant. Pt #1 and #2, who received 2 doses of cemiplimab, returned to baseline levels at week 16 versus at week 12 following a single cemiplimab infusion in Pt #3 and #4. Abbreviations: AE, adverse event; RO, receptor occupancy.

Figure 5.

Gag-stimulated (A), Env-stimulated (B), and Pol-stimulated (C) polyfunctional CD4⁺ and CD8⁺ T-cell responses over time for each participant. Pt #1 (immune responder) had increased gag-, env-, and pol-stimulated polyfunctional CD4⁺ and CD8⁺ T-cell responses following the second cemiplimab infusion. Pt #4 demonstrated increases in human immunodeficiency virus–specific polyfunctional responses coinciding with symptoms consistent with an upper respiratory illness at week 19. Pt #3 and #4 received a single dose of cemiplimab; Pt #1 and #2 received 2 doses of cemiplimab. Abbreviation: AE, adverse event.

Figure 6.

Total cell-associated DNA (A), cell-associated RNA (B), total proviral human immunodeficiency virus type 1 (HIV-1) DNA (C), and intact proviral HIV-1 DNA (D) over time for each participant. Pt #1 (immune responder) had decreased total cell-associated DNA, proviral HIV-1 DNA, and cell-associated RNA. For the proviral HIV-1 DNA results, this participant had a limited number of CD4⁺ T-cell equivalents available at baseline and week 2, as well as an undetectable proviral HIV-1 DNA result at week 12 (represented by an open square in the figure). This participant also had undetectable intact proviral HIV-1 DNA at multiple time points. Abbreviations: AE, adverse event; n.d., not detected.