Syndax Pharmaceuticals Inc., a biopharmaceutical company using epigenetics to treat therapy-resistant cancers, has announced that entinostat, its lead product candidate, in combination with anti-PD1 and anti-CTLA4 monoclonal antibodies, significantly improved treatment outcomes in mouse tumor models.
The study, entitled “Eradication of metastatic mouse cancers resistant to immune checkpoint blockade by suppression of myeloid-derived cells” and published in the PNAS journal by a team of researchers from the Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, showed that treatment of anti-PD-1 and anti-CTLA4 alone was not enough to eliminate aggressive colon and breast metastatic tumors in mice. However, cotreatment with azacitidine and entinostat, an epigenetic modulating drug that selectivetly inhibits histone deacetylases, cured more than 80% of tumor-bearing mice.
The researchers then found that the main targets of epigenetic modulation by entinostast were myeloid-derived suppressor cells (MDSCs), a heterogenous population of immune cells derived from the myeloid lineage that can give rise to dendritic cells, macrophages and neutrophils, but can also give rise to potent immunosuppressive cells as well.
Using entinostast to reduce the amount of circulating MDSCs, along with immune checkpoint inhibitors, also resulted in the eradication of breast tumors in 80% of the mice, leading researchers to conclude that the drug’s elimination of MDSCs is a crucial step in overcoming cancer therapy resistance to immune checkpoint blockade. Importantly, at the concentrations used, entinostast did not show any deleterious effect in the CD8 T cell population, creating the potential for a large therapeutic window.
“We now have strong pre-clinical and anecdotal clinical data that provide potential evidence of entinostat’s immuno-modulatory activity and potential immune-priming effects to anti-cancer immune therapies,” said Peter Ordentlich, Ph.D., co-founder and chief technology officer of Syndax in the company’s press release. “These new results, which are consistent with earlier data demonstrating entinostat inhibition of regulatory T cells, show that epigenetic therapy with entinostat may increase immunogenicity of tumors and reduce resistance to immune therapy through potent inhibition of host immune suppressor cells.”
“We expect additional validation for entinostat’s immune-modulatory activity from ongoing clinical trials including a Phase 2 study evaluating epigenetic priming to the PD-1 blocker nivolumab in non-small cell lung cancer and a Phase 2 study of entinostat in combination with aldesleukin (IL-2) in patients with advanced renal cell cancer. Additional studies of entinostat in combination with anti-PD1/PDL1 therapy are planned”, added Arlene Morris, chief executive officer of Syndax in the press release.
Entinostast has been designated a Breakthrough Therapy by the FDA when used in combination with exemestane for hormone receptor-positive advanced breast cancer, a combination currently being tested in a Phase 3 clinical study aiming to overcome resistance to hormone therapy in men and women suffering from this type of cancer.