Grant: Project Grant

A handful of anti-cancer agents are able to kill cancer cells in a way that elevates the immunogenicity of the dying cancer cells. This form of cancer cell death, called immunogenic cell death, is defined by signals expressed by the dying cells. In this project drug candidates that induce immunogenic cell death are being developed, agents that work even better in the presence of copper. Inducing anti-cancer immunity is an important therapeutic strategy, but the approach requires consideration of drug combinations. A clinically established immunotherapy strategy relies on the use of therapeutic agents designed to target specific proteins called checkpoints. These checkpoints suppress immune responses in cancer. By targeting checkpoints, immune cells are now able to engage and attack cancer cells. These therapeutic agents, referred to as check point inhibitors (CPIs), have revolutionized the treatment of many types of cancers, including metastatic bladder cancer (MBlC). All MBC patients that progress following chemotherapy are given CPIs, however only 20% respond. This project argues that immunotherapy effects will increase if the CPIs are combined with compounds that enhance the immune environment in the tumor by inducing immunogenic cell death. Agents that induce immunogenic cell death will provide optimal therapeutic effects when combined with checkpoint inhibitors. Lead compounds have already been identified but no one understands how copper is influencing immunogenic cell death. Further, the ability of these compounds to achieve improved treatment outcomes when used in combination with CPIs has not been determined. Finally, there remain concerns that the combination may enhance immune related toxic effects and this needs to be studied. The focus of this project is on developing treatments for patients with MBlC. By enhancing immune responses achieved with CPIs, the hope is to increase overall survival of MBC patients from 20% to 40%.