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...
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doaj-82617a89986343a6a08c52f9f5ac5da52021-09-05T11:39:42ZengBMCBMC Cancer1471-24072021-08-0121111710.1186/s12885-021-08702-xThe epigenetic immunomodulator, HBI-8000, enhances the response and reverses resistance to checkpoint inhibitorsReid P. Bissonnette0Rosemary M. Cesario1Bob Goodenow2Farbod Shojaei3Mireille Gillings4HUYABIO International, LLCHUYABIO International, LLCHUYABIO International, LLCHUYABIO International, LLCHUYABIO International, LLCAbstract 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.https://doi.org/10.1186/s12885-021-08702-xHistone deacetylaseHDACEpigeneticsPD-1PD-L1Immune checkpoint |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Reid P. Bissonnette Rosemary M. Cesario Bob Goodenow Farbod Shojaei Mireille Gillings |
spellingShingle |
Reid P. Bissonnette Rosemary M. Cesario Bob Goodenow Farbod Shojaei Mireille Gillings The epigenetic immunomodulator, HBI-8000, enhances the response and reverses resistance to checkpoint inhibitors BMC Cancer Histone deacetylase HDAC Epigenetics PD-1 PD-L1 Immune checkpoint |
author_facet |
Reid P. Bissonnette Rosemary M. Cesario Bob Goodenow Farbod Shojaei Mireille Gillings |
author_sort |
Reid P. Bissonnette |
title |
The epigenetic immunomodulator, HBI-8000, enhances the response and reverses resistance to checkpoint inhibitors |
title_short |
The epigenetic immunomodulator, HBI-8000, enhances the response and reverses resistance to checkpoint inhibitors |
title_full |
The epigenetic immunomodulator, HBI-8000, enhances the response and reverses resistance to checkpoint inhibitors |
title_fullStr |
The epigenetic immunomodulator, HBI-8000, enhances the response and reverses resistance to checkpoint inhibitors |
title_full_unstemmed |
The epigenetic immunomodulator, HBI-8000, enhances the response and reverses resistance to checkpoint inhibitors |
title_sort |
epigenetic immunomodulator, hbi-8000, enhances the response and reverses resistance to checkpoint inhibitors |
publisher |
BMC |
series |
BMC Cancer |
issn |
1471-2407 |
publishDate |
2021-08-01 |
description |
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. |
topic |
Histone deacetylase HDAC Epigenetics PD-1 PD-L1 Immune checkpoint |
url |
https://doi.org/10.1186/s12885-021-08702-x |
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