The epigenetic immunomodulator, HBI-8000, enhances the response and reverses resistance to checkpoint inhibitors

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.

A Cell-Based Screen Identifies HDAC Inhibitors as Activators of RIG-I Signaling

“…However, recent evidence suggests that HDAC inhibition may have roles in the tumor microenvironment ( Li et al, 2021 ). For instance, it has been shown that HDAC inhibition potentiates immunotherapy responses in CT26 and MC38 tumor models ( Bissonnette et al, 2021 ). Our observations introduce the possibility that HDAC inhibition also contribute type I interferons to activate the immune microenvironment.…”

HBI-8000, HUYABIO Lead Clinical Program, Is a Selective Histone Deacetylase Inhibitor With Therapeutic Benefits in Leukemia and in Solid Tumors

“…Compared to single agent CPI monotherapy, HBI-8000 significantly inhibited tumor growth when combined with the above antibodies (23). Mechanistic analysis of tumors using nanoString gene expression showed upregulation of genes responsible for dendritic cell activity, natural killer cells, and cytotoxic T cells in HBI-8000 monotherapy and in combination groups (23). Interestingly, expression of this group of genes was downregulated in the anti-PD1 monotherapy group, further confirming role of HBI-8000 in the induction of activity of key components of tumor immunity (23).…”

“…MC38, CT26, and A20) to investigate its activity in tumor immunity. Compared to single agent CPI monotherapy, HBI-8000 significantly inhibited tumor growth when combined with the above antibodies (23). Mechanistic analysis of tumors using nanoString gene expression showed upregulation of genes responsible for dendritic cell activity, natural killer cells, and cytotoxic T cells in HBI-8000 monotherapy and in combination groups (23).…”

“…Mechanistic analysis of tumors using nanoString gene expression showed upregulation of genes responsible for dendritic cell activity, natural killer cells, and cytotoxic T cells in HBI-8000 monotherapy and in combination groups (23). Interestingly, expression of this group of genes was downregulated in the anti-PD1 monotherapy group, further confirming role of HBI-8000 in the induction of activity of key components of tumor immunity (23). Thus, it appears that HBI-8000 plays an important role in converting the tumor microenvironment from cold (immunosuppressive) to hot when combined with CPIs.…”

Acquired resistance for immune checkpoint inhibitors in cancer immunotherapy: challenges and prospects

“…For example, HBI-8000 is a novel, orally bioavailable class I selective histone deacetylase inhibitor, which directly modifies antitumor activity by inducing apoptosis, cell cycle arrest, and resensitization to apoptotic stimuli in adult T cell lymphoma patients. This compound has been shown to augment the activity of ICIs targeting either PD-1, PD-L1 or CTLA-4, and significantly increase tumor regression [106].…”