Researchers from Johns Hopkins University in Baltimore have found that adding the histone deacetylase inhibitor entinostat (ENT) to checkpoint inhibition decreases tumor burden and improves survival in human epidermal growth factor receptor 2 (HER2)-positive breast cancer models. The findings were reported during the San Antonio Breast Cancer Symposium on Wednesday, December 6.
Although checkpoint inhibition has shown some efficacy in metastatic breast cancer, less is known about its role in breast cancer as compared with other solid tumors, where it is considered very successful in treating naturally immunogenic cancers by attracting T cells into the tumor microenvironment. Incorporating checkpoint inhibition into breast cancer treatment has been a challenge for oncologists and researchers because most breast cancers are not highly immunogenic. This is likely because of an immunosuppressive microenvironment and a lack of tumor antigen expression and recognition. One strategy to circumvent this is to transform the tumor microenvironment through epigenetic modulation to affect activation and trafficking of myeloid derived suppressor cells (MDSCs), which are known to alter the immunogenicity of the tumor microenvironment and sensitize tumors to checkpoint modulation.
The researchers hypothesized that combination therapy would prime the tumor microenvironment by altering infiltration and function of MDSCs, which could then lead to a robust T-cell response. They used a HER-2/neu transgenic mouse model with tumor challenge of syngeneic cell lines to test the efficacy of different combinations of an ENT and antiprogrammed cell death (PD)-1 and anticytotoxic T-lymphocyte-associated protein 4 (a-CTLA-4) antibodies, with and without anti-HER2 antibodies. They reported significant improvement in survival and delay in tumor growth in mice treated with this combination. Adding anti-HER2 therapy to the ENT/checkpoint inhibitor combination also improved survival and delayed tumor growth.
The addition of ENT to checkpoint inhibition led to increased infiltration of granulocytic-MDSCs into the tumor microenvironment. They further demonstrated an increase in CD8+ T effector cells in mice treated with combination therapy. Flow cytometric evaluation of markers of T-cell activation, exhaustion, and MDSC function demonstrated increased T-cell activation, exhaustion, and myeloid function, but the researchers were unclear about how that impacts the phenotype observed in the study mice. Future studies are needed to fully understand the genetic alterations responsible for these results.