A modified IL-18 drug in combination with CTLA-4 blockade enhances anti-tumor efficacy in preclinical models of renal cell carcinoma

Abstract Background Cytokine-based drugs are currently being explored as alternative cancer immunotherapies. While the cytokine interleukin-18 (IL-18) has immunostimulatory effects, it is negatively regulated by a secreted high-affinity binding protein, IL-18BP, that functions an immune checkpoint limits IL-18’s efficacy therapeutic. A modified version of IL-18, termed “decoy-resistant” or DR-18, can avoid trapping IL-18BP while still maintaining its signaling potential, recently been developed. DR-18 shown promising preclinical activity in melanoma and colorectal murine models, including potential synergy with anti-PD-1 therapy, Phase I trials. In this study, we aim to test determine cellular mechanism action combination inhibitors (ICIs) immunocompetent models renal cell carcinoma (RCC), goal establishing basis for testing these combinations early phase clinical Methods We engrafted tumors subcutaneously using two different syngeneic, RCC models: Renca RAG. Mice were treated single-agent single- dual-agent anti-CTLA-4. Tumor growth survival monitored. model, plasma was collected at time-points cytokine/chemokine levels profiled 31-plex discovery assay. Single-cell RNA TCR sequencing also performed on tumors. Additionally, depletion studies conducted model antibodies targeting CD8, CD4, NK cells, interferon-gamma. Results monotherapy modestly inhibited tumor prolonged survival. The effects comparable ICIs. Adding PD-1 blockade did not enhance whereas addition anti-CTLA-4 significantly increased anti-tumor effects. Triple-therapy (DR-18 plus anti-CTLA-4) further inhibit prolong compared doublet anti-CTLA-4). RAG more sensitive ICIs but produced similar results, again showing modest enhanced benefit combining anti-PD-1. Cytokine/chemokine profiling revealed elevated IP-10 (CXCL10) MIG (CXCL9) after one cycle control treatments, suggesting chemokines may be key mediators response. transcriptomic analysis demonstrated changes intra-tumoral T cell, macrophage, granulocyte populations relative other regimens, enrichment CD8+ precursor terminally exhausted cells neutrophil population associated interferon signaling. single-cell showed reduction clonotype diversity treatments. Immune identified interferon-gamma, CD4+ equally required Conclusions identify IL-18-based drug engineered resistance decoy-receptor having RCC. This regimen pro-inflammatory microenvironment. Further investigation ongoing elucidate fully lay groundwork DR-18-based therapy future, novel partner agents outside anti-PD-1/CTLA-4 ICI-resistance could particularly informative clinically relevant.