The SUMOylation inhibitor subasumstat potentiates rituximab activity by IFN1-dependent macrophage and NK cell stimulation

Abstract

SUMOylation is a reversible post-translational modification that has been implicated in the regulation of various cellular processes including inflammatory responses and expression of Type I interferons (IFN1). In this report, we have explored the activity of the selective small molecule SUMOylation inhibitor subasumstat (TAK-981) in promoting antitumor innate immune responses. We demonstrate that treatment with TAK-981 results in IFN1-dependent macrophage and NK cell activation, promoting macrophage phagocytosis and NK cell cytotoxicity in ex vivo assays. Furthermore, pre-treatment with TAK-981 enhanced macrophage phagocytosis or NK cell cytotoxicity against CD20-positive target cells in combination with the anti-CD20 antibody rituximab. In vivo studies demonstrated enhanced antitumor activity of TAK-981 and rituximab in CD20-positive lymphoma xenograft models. Combination of TAK-981 with anti-CD38 antibody daratumumab also resulted in enhanced antitumor activity. TAK-981 is currently being studied in phase 1 clinical trials (NCT03648372, NCT04074330, NCT04776018, and NCT04381650) for the treatment of patients with lymphomas and solid tumors.

SUMOylated IL-33 in the nucleus stabilizes the transcription factor IRF1 in hepatocellular carcinoma cells to promote immune escape

“…SUMOylation suppressors (ML-792 and TAK-981) have been tested in xenograft tumors ( 41 , 42 ), particularly in combination with checkpoint inhibitors like anti–PD-1 (the receptor for PD-L1), which resulted in improved survival of mice bearing syngeneic CT26 and MC38 tumors ( 43 ). However, although current SUMO inhibitors are selective for SUMOylation, they are not specific for a particular SUMOylated protein.…”

Small-molecule SUMO inhibition for biomarker-informed B-cell lymphoma therapy

“…Notably, SUMO inhibition alone or administered as combination therapy with rituximab, a standard therapy for BCL patients, showed remarkable efficacy in preclinical DLBCL xenograft models. 25 , 41 Besides, SUMO inhibition is currently tested in various clinical trials (clinicaltrials gov. Identifier: NCT03648372, NCT04074330, NCT04381650), emphasizing the relevance of our findings for biomarker-informed clinical applications.…”

Role and Mechanisms of Tumor-Associated Macrophages in Hematological Malignancies

“…further proved in a phase 1b/2, open-label, dose-escalation and expansion study that TAK-981 plus rituximab resulted in promising clinical activity (ORR 29%) in the R/R NHL ( 134 ). Combination of TAK-981 with anti-CD38 antibody daratumumab also resulted in protective clinical antitumor immune response ( 135 ). TAK-981 increased phagocytic activity of macrophages and natural killer cell cytotoxicity via IFN-1 signaling, which could be a promising treatment for patients with hematological malignancies ( 136 ).…”