Cancer Immune Evasion in Gastrointestinal Cancer: Can this be Overcome by Combination of Histone Deacetylase and Immune Checkpoint Inhibitors?

Although immune checkpoint inhibitors have been used for the treatment of gastrointestinal malignancies, clinical benefit has been modest compared to other tumour sites. Microsatellites high cancers have shown a better response to immunotherapy but they make up a small percentage of this group of tumours. Efforts to improve results have been made, particularly through the use of combination therapy and such an example would be the combination with anti-VEGF agents which have shown some promise in gastric cancers. Histone deacetylase inhibitors (HDACi) have been shown to be effective anti-cancer agents particularly for haematological malignancies with multiple anti-tumour mechanisms of action including the induction of apoptosis, cell cycle arrest and the upregulation of major histocompatibility complex (MHC) in tumour cells. Although there has not been much clinical success in the context of gastrointestinal cancers, there is preclinical evidence to suggest that combination therapy with traditional chemotherapy agents may have some therapeutic benefit. However, the combination of HDACi with immune checkpoint inhibitors has not been studied. Both HDACi and immune checkpoint inhibitors have already demonstrated satisfactory safety profiles and furthermore, clinical activity of HDACi can be monitored by the use of biomarkers. Therefore, it has been hypothesised that by combining the two treatment agents together, synergism may be observed in the form of improved host immune anti- tumour response as a result of enhanced immunogenicity conferred by HDACi, which will ultimately result in effective tumour killing.

Keywords: Cancer, Histone Deacetylase, Immune Checkpoint Blockade, PD1.