Combination of Anti-PD-L1 Antibody with IMiD® Immunomodulatory Drugs, HDAC Inhibitor ACY-1215, Bortezomib, or Toll-like Receptor 9 Agonist Enhances Anti-Tumor Immunity and Cytotoxicity in Multiple Myeloma

IntroductionDysfunctional T cells and Natural Killer (NK) cells in MM, together with functionally defective plasmacytoid dendritic cells (pDCs), contribute to the immune suppression in MM (Chauhan et al, Cancer Cell 2009, 16:309-323; Ray et al, Leukemia 2014, 28: 1716-1724).The mechanism and the role of immunoregulatory molecules mediating pDC-T cell and pDC-NK cell interactions in MM are now defined. Programmed cell death protein 1 (PD-1) is highly expressed on MM patient T cells and NK cells; and both pDCs and MM cells express PD-1 ligand PD-L1 (B7-H1). PD-L1 interaction with PD-1 results in bidirectional inhibitory responses in T cells. Our study showed that pDCs confer T cell and NK cell immune suppression in the MM BM milieu by engaging immune checkpoints viaPD-L1/PD-1 signaling axis (Ray et al, Leukemia 2015, 29:1441-1444). Importantly, blockade of PD-L1-PD-1 using anti-PD-L1 Ab generates MM-specific CD8+ CTL activity, as well as enhances NK-cell-mediated MM cell cytolytic activity. Anti-MM therapies may modulate MM-host immune responses, which raises the possibility that efficacy of anti-PD-Ll Ab can be improved by combining these therapies with immune-stimulating agents. Here we examined the impact of combining immune checkpoint blockade with lenalidomide, pomalidomide, bortezomib, HDAC inhibitor ACY-1215, or Toll-Like Receptor 9 agonists on anti-tumor immunity and cytotoxicity in MM.