SUMOylation is a reversible post-translational modification that regulates protein function by covalent attachment of the small ubiquitin-like modifier (SUMO) protein to protein substrates. TAK-981 is a novel, selective small molecule inhibitor of the SUMOylation enzymatic cascade, which has demonstrated induction of potent anti-tumor immunity in preclinical models. In this study, we evaluated changes in immune cell composition and states after TAK-981 treatment in preclinical models. In both mouse bone-marrow and human peripheral blood mononuclear cell derived dendritic cells (DCs), TAK-981 treatment ex vivo induced markers of activation and maturation including CD40, CD80 and CD86, as well as increased secretion of inflammatory cytokines like IP-10, MCP1, MIP-1α, MIP1β, IFNα and IFNβ. These effects were reversed by an interferon alpha receptor (IFNAR) blocking antibody, demonstrating dependence of TAK-981 induced pharmacodynamic effects on Type I interferon signaling in DCs. In vivo, a single sub-cutaneous injection of TAK-981 in naïve Balb/c mice at the brachial lymph nodes induced activation of DCs, measured as significant increases in CD40 and CD86 expression. Concomitantly, an increase in expression of the early lymphocyte activation marker CD69 was observed on T cells and NK cells, demonstrating pleiotropic effects of TAK-981 on immune cells. Increased expression of CD69 was also observed in purified human T and NK cells treated with TAK-981 ex vivo. To investigate if enhanced activation of DCs by TAK-981 leads to improved cross-presentation of exogenous antigens, we challenged naïve C57BL/6 mice with chicken-ovalbumin (OVA) protein alone or in combination with TAK-981. Interestingly, an increase in the frequency of Kb-SIINFEKL tetramer positive CD8 T cells was observed in the draining lymph nodes overnight, and in the spleen on day 14, after treatment with TAK-981+OVA, suggesting that TAK-981 promotes cross-presentation of SIINFEKL, the class-I MHC epitope of OVA, to cognate antigen-specific CD8 T cells. We also observed an increase in the frequency of CD8α+ DCs loaded with the peptide ‘SIINFEKL’ on H-2Kb (class-I MHC of C57BL/6 mice), providing direct evidence for enhanced antigen-cross presentation. Similar findings were observed with TAK-981 administered either sub-cutaneously or via the therapeutic route of intra-venous injection in the above OVA immunization model. These results suggest a mechanism by which TAK-981 may promote anti-tumor immune responses in mice via enhanced cross-presentation of exogenous antigens released by dying tumor cells, leading to priming and activation of antigen reactive cytotoxic T cells. Currently, TAK-981 is being evaluated in Phase 1 clinical trials in adult patients with metastatic solid tumors or lymphomas (ClinicalTrials.gov Identifier: NCT03648372).
Citation Format: Mithun Khattar, Keli Song, Stephen Grossman, Kristina Xega, Xingyue He, Neeraja Idamakanti, Dennis Huszar. TAK-981: A first in class SUMO inhibitor in Phase 1 trials that promotes dendritic cell activation, antigen-presentation, and T cell priming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3252.