Programmed cell death protein 1 and Interleukin-18 receptor (PD-1/IL-18R)

The target 'Combined PD-1 and IL-18 receptor engagement on the same T cell' refers to a dual-targeting therapeutic strategy involving Programmed cell death protein 1 (PD-1) and the Interleukin-18 receptor (IL-18R) [1, 2]. This approach typically employs a bispecific fusion protein, such as PD1-IL18v (RG6627), to simultaneously block the inhibitory PD-1 pathway and activate the pro-inflammatory IL-18 pathway specifically on tumor-reactive T cells [3, 4]. By engaging both receptors in 'cis' (on the same cell), the therapy aims to revitalize exhausted CD8+ T cells, which are known to upregulate both PD-1 and IL-18R in the tumor microenvironment [1, 5]. This dual mechanism synergistically enhances T cell proliferation, metabolic fitness, and effector functions like interferon-gamma production, potentially overcoming resistance to standard checkpoint inhibitors [1, 3]. Clinically, this strategy is being explored to treat various solid tumors while minimizing the systemic toxicity associated with non-targeted cytokine therapy [4, 6]. The specificity of this engagement ensures that the potent IL-18 signal is delivered primarily to the cells most capable of anti-tumor activity, thereby improving the therapeutic index [1, 4]. This target represents a significant advancement in next-generation immunotherapies that combine checkpoint blockade with localized cytokine agonism [3, 5]. Sources: [1] Nature (2024) 'A PD-1–targeted IL-18 fusion protein delivers a potent cytokine signal to exhausted T cells' [2] UniProt: PDCD1 (Q15116) and IL18R1 (Q13342) [3] Cancer Cell (2022) 'Targeted IL-18 improves anti-tumor effector T cell function' [4] Roche Pipeline / ClinicalTrials.gov (NCT05866613 for RG6627) [5] PubMed: 'IL-18 and PD-1 synergy in T cell exhaustion' [6] StatPearls: 'Immune Checkpoint Inhibitors'

Other names

PD-1/IL-18R cis-engagementPD1-IL18 fusion proteinPD-1-targeted IL-18PD1-IL18vPD-1 and IL-18 receptor dual target

Simultaneous blockade of the PD-1 inhibitory checkpoint and agonism of the IL-18 receptor on the same T cell (cis-engagement) to synergistically enhance effector function and reverse exhaustion.