Grant: Project Grant

Immune checkpoint inhibitors (ICIs) represent a new class of typically antibody-based agents that restores the body's natural immune response directed at cancer cells. They do so by blocking signals, often sent by cancer cells to immune cells to dampen immune responses directed at them. ICIs thus allow for the release of tumor-directed immune responses. These blocking agents, namely anti-PD-1, anti-PD-L1 and anti-CTLA-4 monoclonal antibodies, have led to impressive clinical results in patients with advanced melanoma and lung cancer, particularly when combined together or with other established cancer therapies. However, these treatments only prolong patient survival in certain types of cancers. One key reason is that our immune system has evolved many checkpoints to control its responses directed at infections or to dampen them to avoid self-immunity. One key checkpoint pathway that works in parallel with PD-1 and PD-L1 involves a molecule called VISTA. We propose to develop VISTA inhibitors since the expression of this molecule has recently been shown to increase on both immune and cancer cells of prostate cancer patients that do not respond to anti-CTLA-4 therapy. This finding indicates that tumor cells are evading recognition from immune responses by de-activating immune cells such as T cells through their VISTA pathway. We propose to develop and test several classes of VISTA inhibitors that will work with approved ICIs to restore immunity towards tumors.