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BMC Cancer

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01-12-2021 | Immunomodulator | Research

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

Authors: Reid P. Bissonnette, Rosemary M. Cesario, Bob Goodenow, Farbod Shojaei, Mireille Gillings

Published in: BMC Cancer | Issue 1/2021

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.

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Title: The epigenetic immunomodulator, HBI-8000, enhances the response and reverses resistance to checkpoint inhibitors
Authors: Reid P. Bissonnette
Rosemary M. Cesario
Bob Goodenow
Farbod Shojaei
Mireille Gillings
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Immunomodulator
Checkpoint Inhibitors
Epigenetics
Published in: BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-021-08702-x

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