Tumors employ diverse strategies to suppress and evade the immune system’s ability to recognize and destroy tumor cells. Immune-suppressive Foxp3+ regulatory T cells (Tregs) in the tumor microenvironment correlate with poor prognosis in solid tumors. Therefore, selective depletion of tumor-associated Tregs or impairment of Treg function is considered an attractive cancer immunotherapy approach. The pro-tumorigenic deubiquitylase (DUB) USP7 is also essential for Treg functions. USP7 controls Treg function largely by regulating post-translational modification of Foxp3 and TIP60. Deletion of USP7 in Tregs results in impairment of Treg functions and autoimmunity in mice. Progenra has developed potent, selective covalent irreversible USP7 inhibitors that impair Treg functions ex vivo and in vivo. Most importantly, USP7 inhibitors exhibit robust antitumor activity against several syngeneic solid tumor models in immunocompetent mice. In addition, Progenra’s USP7 inhibitors enhance the efficacy of anti-PD1 antibody, anti-CTLA4 antibody, and cancer vaccines. These studies strongly suggest that USP7 inhibitors alone or in combination regimens can improve the efficacy and expand the scope of cancer immunotherapy.

Citation Format: Suresh Kumar, Jian Wu, Feng Wang, Liqing Wang, Lee Chen, Ivan Sokirniy, Hui Wang, David Sterner, Charles Grove, Brigid Cunnion, Joseph Weinstock, Michael Mattern, Wayne Hancock. Covalent irreversible usp7 inhibitors for cancer immunotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B202.