Bio-P-08 - Mode-of-action of HDAC inhibitor resminostat in CTCL

Abstract

Cutaneous T cell lymphoma (CTCL) is a non-Hodgkin lymphoma characterized by malignant skin-homing T cells with an increasing bias towards the T helper cell type 2 (Th2) during disease progression. Patients with advance CTCL have a high disease burden and the majority of CTCL patients suffer from severe itching (pruritus). A key challenge in the treatment of advanced CTCL is to maintain and to stabilize initial therapeutic responses after systemic treatment. Addressing this clinical need, the oral class I, IIb, IV HDAC inhibitor resminostat is currently under clinical evaluation for disease control after systemic therapy (RESMAIN, NCT02953301). Here, the mode-of-action of resminostat was explored. Several CTCL cell lines representing mycosis fungoides (MF) and Sézary syndrome (SS) were used in cell biological and molecular assays. HDAC inhibitors are epigenetic drugs that alter the chromatin landscape and the expression of genes. Indicating an interference with epigenetic processes, resminostat induced hyperacetylation on specific histone residues linked with transcriptional regulation. Whole transcriptome analysis upon resminostat treatment uncovered changes in oncogenic signaling pathways and in the expression of genes associated with the pathogenesis of CTCL. The expression of several skin-homing receptors, which mediate the infiltration of malignant T cells into the skin, was reduced by resminostat. Furthermore, resminostat up-regulated a gene expression signature representative of Th1 cell type and down-regulated genes of the Th2 cell type, thus favoring the beneficial Th1 T cell phenotype. In agreement with this observation, resminostat decreased the mRNA level and protein secretion of the Th2 and itch-mediating cytokine IL-31 suggesting that resminostat might improve pruritus. Moreover, resminostat treatment resulted in anti-proliferative and pro-apoptotic effects in both MF and SzS cells. In addition to counteracting intrinsic pathogenic pathways in malignant CTCL cells, we found that resminostat enhanced natural killer cell-mediated lysis, thus promoting the innate immune response towards malignant cells. In contrast to reports for other HDAC inhibitors, resminostat did not reduce the viability or function of NK cells but directly positively affected their cytolytic function. Moreover, resminostat up-regulated the expression NKG2D-ligands on cancer cells and, thereby, facilitates the recognition of cancer cells by NK cells. Interestingly, the combination of resminostat with opsonizing antibodies (e.g. Mogamulizumab, IPH4102) improved the lysis of CTCL cells in NK cell assays, suggesting a potential of resminostat's combinations with opsonizing antibodies. Taken together, these data corroborate that resminostat has the potential to counteract the malignant T cell population in CTCL. In conclusion, our preclinical data support the hypothesis that resminostat treatment will improve or stabilize CTCL and its symptoms.