Combination of a Novel HDAC 6 Inhibitor ACY-241 with Anti-PD-L1 Antibody Enhances Anti-Tumor Immunity and Cytotoxicity in Multiple Myeloma

IntroductionHistone deacetylases (HDACs) are attractive therapeutic targets, and selective HDAC inhibitors (HDACi), alone or in combination with other anti-cancer agents are useful treatment strategies in multiple myeloma (MM). HDACs are also involved in immune regulation in hematological malignancies. For example, blockade of HDACs upregulate immunecheckpoints such as PD-1 ligand (PD-L1). Furthermore, combination of HDACi with PD-1/PD-L1 checkpoint blockade significantly improves immunotherapy in a murine B16F10 model [Woods et al,Cancer Immunol Res. 2015; 3:1375-85]. Here we utilized an orally bioavalable HDAC6 selective inhibitor ACY-241 currently under clinical trials to examine whether combination of ACY-241 with anti-PD-L1 antibody enhances anti-MM immunity. For these studies, we utilized our previously published co-culture models of immune effector cells (plasmacytoid dendritic cells, pDCs, T cells, NK cells) and MM cells (Chauhan et al, Cancer Cell 2009, 16:309-323; Ray et al, Leukemia 2015, 29:1441-1444). Specifically, in MM we have shown that: 1) PD-1 is highly expressed on T and NK cells, and both pDCs and MM cells express PD-L1; 2) MM-pDCs confer T- and NK cell immune suppression via PD-L1/PD-1 immune checkpoints and 3) blockade of PD-L1-PD-1 signaling axis by anti-PD-L1 Ab generates MM-specific CD8+ CTL activity, as well as enhances NK-cell-mediated MM cell cytolytic activity. We here examined whether combination of ACY-241 with anti-PD-L1 Ab increases anti-tumor immunity and cytotoxicity in MM.