Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2019-03

AUTHORS

Diana Llopiz, Marta Ruiz, Lorea Villanueva, Tamara Iglesias, Leyre Silva, Josune Egea, Juan J. Lasarte, Perrine Pivette, Véronique Trochon-Joseph, Bérangère Vasseur, Graham Dixon, Bruno Sangro, Pablo Sarobe

ABSTRACT

Immune checkpoint inhibitors are currently tested in different combinations in patients with advanced hepatocellular carcinoma (HCC). Nivolumab, an anti-PD-1 agent, has gained approval in the second-line setting in the USA. Epigenetic drugs have immune-mediated antitumor effects that may improve the activity of immunotherapy agents. Our aim was to study the therapeutic efficacy of checkpoint inhibitors (anti-CTLA-4 and anti-PD-1 antibodies) in combination with the histone deacetylase inhibitor (HDACi) Belinostat. In a subcutaneous Hepa129 murine HCC model, we demonstrated that Belinostat improves the antitumor activity of anti-CTLA-4 but not of anti-PD-1 therapy. This effect correlated with enhanced IFN-γ production by antitumor T-cells and a decrease in regulatory T-cells. Moreover, the combination induced early upregulation of PD-L1 on tumor antigen-presenting cells and late expression of PD-1 on tumor-infiltrating effector T-cells, suggesting the suitability of PD-1 blockade. Indeed, Belinostat combined with the simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection. These results provide a rationale for testing Belinostat in combination with checkpoint inhibitors to enhance their therapeutic activity in patients with HCC. More... »

PAGES

379-393

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00262-018-2283-0

DOI

http://dx.doi.org/10.1007/s00262-018-2283-0

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1110580098

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30547218


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