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.