ABSTRACT
BACKGROUND: Treatment with immune checkpoint inhibitors (ICIs) targeting CTLA-4 and the PD-1/PD-L1 axis is effective against many cancer types. However, due in part to unresponsiveness or acquired resistance, not all patients experience a durable response to ICIs. HBI-8000 is a novel, orally bioavailable class I selective histone deacetylase inhibitor that directly modifies antitumor activity by inducing apoptosis, cell cycle arrest, and resensitization to apoptotic stimuli in adult T cell lymphoma patients. We hypothesized that HBI-8000 functions as an epigenetic immunomodulator to reprogram the tumor microenvironment from immunologically cold (nonresponsive) to hot (responsive). METHOD: Mice bearing syngeneic tumors (MC38 and CT26 murine colon carcinoma and A20 B-cell lymphoma were treated daily with HBI-8000 (orally), alone or in combination with PD-1, PD-1 L, or CTLA-4 antibodies. MC38 tumors were also analyzed in nanoString gene expression analysis. RESULTS: HBI-8000 augmented the activity of ICI antibodies targeting either PD-1, PD-L1 or CTLA-4, and significantly increased tumor regression (p < 0.05) in the above models. Gene expression analysis of the treated MC38 tumors revealed significant changes in mRNA expression of immune checkpoints, with enhanced dendritic cell and antigen-presenting cell functions, and modulation of MHC class I and II molecules. CONCLUSIONS: These findings suggest that HBI-8000 mediates epigenetic modifications in the tumor microenvironment, leading to improved efficacy of ICIs, and provide strong rationale for combination therapies with ICIs and HBI-8000 in the clinical setting. PRECIS: As an HDACi, HBI-8000 plays an important role in priming the immune system in the tumor microenvironment. The current preclinical data further justifies testing combination of HBI-8000 and ICIs in the clinic.
Subject(s)
Benzamides/pharmacology , Colonic Neoplasms/drug therapy , Drug Resistance, Neoplasm/drug effects , Immune Checkpoint Inhibitors/pharmacology , Immunologic Factors/pharmacology , Pyridines/pharmacology , Animals , Apoptosis , Cell Proliferation , Colonic Neoplasms/immunology , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Epigenesis, Genetic , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Nude , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
HBI-8000 is a small molecule inhibitor of class I HDACs and has been approved for the treatment of PTCL, ATL and, in combination with exemestane, in a subpopulation of breast cancer. Given the roles of HDACs in normal and cancerous cells, there are currently multiple clinical trials, by HUYABIO International, to test the efficacy of HBI-8000 in monotherapy or in combination settings in leukemias and in solid tumors. The current review is focused on the applications of HDACi HBI-8000 in cancer therapy and its potential in combination with DDR agents.
