Regulatory T (Treg) cells keep immune responses to foreign antigens in check. This includes attacks from viruses, commensal bacteria, and foreign bodies as well as cancer cells. This fine-tuning mechanism allows a protective but transient inflammation, preserving tolerance to the body’s own antigens after infections are cleared.
Cancers – with their many genetic alterations – frequently present themselves to the immune system as foreign. However, tumors are also capable of adapting, co-opting immune suppressive mechanisms to evade detection by the immune system. An important way that cancers do this is by recruiting and subverting Treg to interfere with immune surveillance.
Numerous studies of human cancers have found Treg cell accumulation in and around tumors within the tumor microenvironment. This observation correlates with poor patient prognosis in many cancers, including melanoma, lung and breast cancers. Treg cells inhibit other T cells from killing tumor cells. These data have triggered research into curbing Treg cell activity in an effort to unleash a therapeutic antitumor immune response. By removing their suppressive effects and “taking the brakes off” of an otherwise effective antitumor response, a therapy targeting Treg cells should help eradicate tumors.
Strategies to suppress Treg cells have included modulating cytokine signaling, depletion with antibodies, or treatment with cytotoxic agents. However, these approaches frequently impact other cell populations required for robust immune responses while triggering side effects due to the normal role of Treg cells in healthy tissues. Novel approaches to selectively interfere with tumor-associated Treg cells are therefore of interest.
We have taken a comprehensive approach to target Treg cells, with several programs advancing through discovery and development. Our lead oral small molecule compound, FLX475, blocks a receptor called CCR4. The CCR4 receptor, found on nearly all human Treg cells, binds to secreted factors made in the tumor microenvironment that encourage Treg cells to come to the tumor. By blocking the secreted factors from binding, we believe that FLX475, will prevent Treg cell accumulation in tumors and enhance tumor immunity. Our second compound, a small molecule compound that blocks an enzyme called USP7, interferes with specific mechanisms that allow Treg cells to suppress antitumor T cells. In addition, we are advancing discovery programs targeting the Treg pathway.