Il-18 tumor immunotherapy is not effective? Yale scientists have discovered key proteins.

IL-18 is a cytokine that has a special role in mobilizing T cells and natural killer cells against infectionBecause of this activity, some pharmaceutical companies have tried to use IL-18 for cancer treatmentHowever, this approach has not shown any benefits in clinical trials"This is a major paradox for us," said Aaron Ring, an assistant professor of immunobiology and pharmacology at Yale UniversityBecause IL-18 sends an extremely powerful inflammatory signal to the immune cells that attack tumors, previous clinical trials have not shown an response to natural IL-18This fact makes us aware that tumors are adopting immune responsesAaron Ring (Photo: X-MOL) June 24 , Aaron Ring's team published a paper in Nature that they found a interfering protein that prevents IL-18 from reaching tumors, and have designed a variant of IL-18 that is not blocked by the interfering protein, which significantly reduces tumors in mice that are resistant to current immunotherapyThis discovery is of great significance for IL-18 targets and for the entire field of cytokine immunotherapyPhoto Source: Nature The study first confirmed through bioinformatics and immunology experiments that IL-18 and its receptors expressed increased expression in tumor-immersed lymphocytes, suggesting that IL-18 was associated with the body's anti-tumor immunityThe Ring team then began studying how tumors blockIL-18They found that in many cancer microenvironments, there is a "fake receptor" called IL-18 binding protein (IL-18 binding protein, IL-18BP), which induces IL-18, blocks IL-18's ability to bind to real receptors on its immune cells and activate the immune responsePhoto Source: Nature Ring: "We believe that IL-18 is the right pathway, but IL-18BP is an obstacle to its activitySo we wanted to know if we could synthesize an IL-18 that could overcome the problemTo solve this problem, the researchers used a method called directional evolution to search for about 300 million different forms of IL-18 mutants, looking for variants that bind only to the real IL-18 receptor, not IL-18BPIn the process, an improved version called DR-18 stands out, and it has a high binding tendency to il-18 receptors, maintaining the IL-18's original signal activation without being inhibited by IL-18BPa diagram of the directional evolutionary process(Photo source: Nature) Compared to wild IL-18, DR-18 significantly reduced tumor growth in a variety of mouse tumor models, including mice resistant to conventional immunotherapy, and even completely eradicated tumors in many mice Further analysis showed that DR-18 therapy changed the microenvironment of the tumor It greatly activates a variety of immune cells in the tumor, including T lymphocytes, macrophages, and neutrophils DR-18 reimagines the vast majority of tumor-immersed CD8 T cells into strong-effect cell groups, reducing the depletion of CD8 T cell groups In addition, DR-18 increases the number of important stem cell-like T-cell groups that maintain an effective anti-tumor response It is reported that the clinical transformation of this study is also actively advancing The dr-18's global patent was granted in 2019 and granted to Simcha Therapeutics Biotech, founded by Aaron Ring The company has just raised $25 million in round A financing and is expected to push its leading project, the Humanized IL-18 variant ST-067, to clinical in 2021 Related papers: Ting Zhou et al, IL-18BP is a secreted immune checkpoint and barrier to IL-18 immunotherapy Nature (2020) Reference: Blocking a 'jamming signal' can immune system to fight tumors (Source: Medical Press)