作者
Eric S. Lightcap,Pengfei Yu,Stephen Grossman,Keli Song,Mithun Khattar,Kristina Xega,Xingyue He,James M. Gavin,Hisashi Imaichi,James Garnsey,Erik Koenig,Hongru Zhang,Zhen Lu,Priyal Shah,Yu Fu,Michael A. Milhollen,Beryl A. Hatton,Jessica Riceberg,Vaishali Shinde,Cong Liu,James Minissale,Xiaofeng Yang,Dylan B. England,Richard A. Klinghoffer,Steve Langston,Katherine Galvin,Gary Shapiro,Sai Murali Krishna Pulukuri,Serge Y. Fuchs,Dennis Huszar
摘要
SUMOylation, the covalent conjugation of small ubiquitin-like modifier (SUMO) proteins to protein substrates, has been reported to suppress type I interferon (IFN1) responses. TAK-981, a selective small-molecule inhibitor of SUMOylation, pharmacologically reactivates IFN1 signaling and immune responses against cancers. In vivo treatment of wild-type mice with TAK-981 up-regulated IFN1 gene expression in blood cells and splenocytes. Ex vivo treatment of mouse and human dendritic cells promoted their IFN1-dependent activation, and vaccination studies in mice demonstrated stimulation of antigen cross-presentation and T cell priming in vivo. TAK-981 also directly stimulated T cell activation, driving enhanced T cell sensitivity and response to antigen ex vivo. Consistent with these observations, TAK-981 inhibited growth of syngeneic A20 and MC38 tumors in mice, dependent upon IFN1 signaling and CD8+ T cells, and associated with increased intratumoral T and natural killer cell number and activation. Combination of TAK-981 with anti-PD1 or anti-CTLA4 antibodies improved the survival of mice bearing syngeneic CT26 and MC38 tumors. In conclusion, TAK-981 is a first-in-class SUMOylation inhibitor that promotes antitumor immune responses through activation of IFN1 signaling. TAK-981 is currently being studied in phase 1 clinical trials (NCT03648372, NCT04074330, NCT04776018, and NCT04381650) for the treatment of patients with solid tumors and lymphomas.