In cancer settings severe T cell exhaustion is one major road block limiting immunotherapy efficacy. Epigenetic changes happening during T cell effector differentiation lock T cells in a non-programmable state which limits the efficacy of checkpoint blockade. In addition, histone modification has been reported to critically modulate MHC I and II expression on tumor cells and influx of T cells into tumor.

We have previously shown that intratumoral administration of a TLR9 agonist, SD-101, induces T cell responses capable of attacking tumor lesions throughout the body. SD-101, combined with the PD-1 inhibitor pembrolizumab, is currently being investigated in patients with metastatic melanoma and head and neck cancer with encoraging results. Domatinostat (4SC AG) is a well-tolerated orally available selective class I histone deacetylase inhibitor HDACi) with demonstrated anti-tumor activity in hematological cancers as well as in numerous animal models of solid tumors as monotherapy and in combination with checkpoint blockade. Domatinostat is currently being investigated in patients with metastatic melanoma and gastrointestinal cancers in combination with PD(L)-1 antibodies.

This study addresses whether the addition of domatinostat to the SD-101 regimen would potentiate the T cell response induced by SD-101. Studies were conducted in multiple syngeneic models in which tumors grow in multiple site of the body but only one is treated intratumorally with SD-101 and domatinostat is given systemically (oral). SD-101 and domatinostat were given alone or in combination, at clinically relevant dosages. The combination of intratumoral SD-101 and domatinostat induced substantial regression of the primary tumor (injected) and distant site cutaneous tumors, as well as lung metastases

The combination was superior to either agent given alone and led to increased tumor specific cytotoxic CD8 T cells (CTL) infiltrating distant site lesions. CTL’s were characterized by a low exhaustion phenotype, increased proliferative capacity and increased co-expression of cytolytic markers, CD107 and GranzymeB. Gene expression profiling was performed on abscopal tumors using the PanCancer immune profiling panel from Nanostring.

The combination of SD-101 and domatinostat led to upregulation of multiple immune related signatures indicating increased T, NK and dendritic cell functions. Notably, the combination of SD-101 and domatinostat was more efficacious than SD-101 combined with various other epigenetic compounds. The addition of PD-1

blockade to SD-101 and domatinostat further boosted T cell responses leading to rejection in mice with high metastatic burdens. These results suggest that domatinostat acts on SD-101 primed tumor specific CD8+ T cells to expand them, render them more cytolytic and facilitate their infiltration in abscopal tumors.

Citation Format: Émilie Degagné, Jose Romo, Marilena Gallotta, Shravan Kannan, Robert L. Coffman, Cristiana Guiducci. Tumor abscopal responses induced by the TLR9 agonist, SD-101, are strongly potentiated by a HDAC class I inhibitor, domatinostat [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 2259.