Background: The immune profile in the cancer microenvironment continues to be a key predictor of survival and disease progression. Tractinostat, a class I specific histone deacetylase inhibitor (HDI) is being investigated in a phase 1b/2 trial for the treatment of virally associated EBV lymphoma in combination with valganciclovir. Tractinostat also possesses unique qualities as an immune modulator to enhance an anti-viral and anti-tumor immune response.
Methods: This study examined tractinostat in a syngeneic CT26 colon cancer mouse model in combination with an anti-PD-1 monoclonal antibody to evaluate differences in tumor burden. The immune cell profile of the tumor microenvironment was also examined by FACS and specific immune response genes indicative of anti-tumor and anti-viral cell functionality by qPCR.
Results: Compared to anti-PD-1 monotherapy, the combination arm showed a reduction in the average day 21 tumor burden by 93%. When examining the microenvironment, the combination group showed a 3.4-fold increase in activated CD8+ T cells, a 2.2-fold increase in Th1 CD4+ T cells, a 51% reduction in Treg FOXP3 expression and a 3.9-fold increase in interferon gamma expression. Conclusions: Tractinostat was able to improve immunotherapy treatment in a partially checkpoint resistant tumor model. The tumor microenvironment was also specifically directed toward an interferon gamma and activated Th1 response. This suggests future epigenetic enhancement of other immunotherapy treatments in which an anti-viral or anti-tumor T cell response is required or preferred.
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