IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy

Cytokines were the first modern immunotherapies to produce durable responses in advanced cancer, but their application has been hampered by modest efficacy and limited tolerability(1,2). In an effort to identify alternative cytokine pathways for immunotherapy, we found that components of the Interleukin-18 (IL-18) pathway are upregulated on tumor infiltrating lymphocytes (TIL), suggesting that IL-18 therapy could enhance anti-tumor immunity. However, recombinant IL-18 previously failed to demonstrate efficacy in clinical trials(3). Here we show that IL-18BP, a high-affinity IL-18 decoy receptor, is frequently upregulated in diverse human and murine tumors and limits the anti-tumor activity of IL-18 in mice. Using directed evolution, we engineered a ‘decoy-resistant’ IL-18 (DR-18), which maintains signaling potential, but is impervious to inhibition by IL-18BP. In contrast to wild-type IL-18, DR-18 exhibits potent anti-tumor efficacy in mouse tumor models by promoting the development of poly-functional effector CD8(+) T cells, decreasing the prevalence of exhausted CD8(+) T cells expressing TOX, and expanding the pool of stem-like TCF1(+) precursor CD8(+) T cells. DR-18 also enhances NK cell activity and maturation to effectively treat anti-PD-1 resistant tumors that have lost MHC class I surface expression. These results highlight the potential of the IL-18 pathway for immunotherapeutic intervention and implicate IL-18BP as a major therapeutic barrier.