Journal: Nature medicine
This phase 1 exploratory analysis evaluated pembrolizumab in 30 people living with HIV and cancer on suppressive ART (CITN-12 trial, NCT02595866), focusing on HIV reservoir dynamics and immune mechanisms.
Key points:
- Safety and antitumor activity:
- Pembrolizumab was generally well tolerated; most treatment-related adverse events were grade 1–2.
- Objective tumor responses occurred in 5 patients (1 complete response, 4 partial responses).
- Early immune effects (within 24 hours):
- Rapid expansion of proliferating HIV-specific effector CD8 T cells.
- Decrease in plasma TGFβ, a known immunosuppressive cytokine.
- Longer-term immune programs and reservoir effects:
- Among 14 participants followed to end of treatment (44–315 days), 9 showed:
- Early induction and sustained expression of interferon-stimulated genes (ISGs).
- Upregulation of antiviral restriction factors.
- Increased Toll-like receptor (TLR) signaling.
- Associated reduction in the HIV reservoir.
- These data link a durable antiviral/innate immune transcriptional program with measurable HIV reservoir decline under PD-1 blockade.
- Broader relevance:
- Mapping the observed transcriptomic signatures onto >1,000 publicly available single-cell RNA-seq datasets showed that similar anti–PD-1–induced antiviral programs already exist in subsets of individuals across various disease states, suggesting some patients are “pre-primed” for this response.
- The work proposes that sustained ISG activation may be a key mechanism contributing to reservoir reduction and could help prevent viral rebound after ART interruption.
Clinical implication:
- Specific immune signatures (ISG, restriction factors, TLR pathways) may serve as biomarkers to identify people with HIV most likely to achieve HIV reservoir decay with anti–PD-1 therapy, with potential relevance for HIV cure–directed strategies in the oncology setting.