Health
Jump-starting the T cell response in established tumors
Key Points
Checkpoint blockade only works in 10-20% of patients. Consequently, investigators are testing checkpoint inhibitors in combination with drugs like the class I histone deacetylase inhibitor, entinostat (ENT). Unfortunately, the combination of ENT and checkpoint blockade fared poorly in patients with breast or ovarian cancer, despite promising pre-clinical results.
Checkpoint blockade only works in 10-20% of patients. Consequently, investigators are testing checkpoint inhibitors in combination with drugs like the class I histone deacetylase inhibitor, entinostat (ENT). Unfortunately, the combination of ENT and checkpoint blockade fared poorly in patients with breast or ovarian cancer, despite promising pre-clinical results. Here we show that ENT enhances CD8+ T cell responses by maintaining a progenitor-like population of CD8+ T cells that supplies activated effector T cells to tumors for prolonged periods. Surprisingly, the anti-tumor effects of ENT are only experienced when delivered during a narrow window that occurs after T cell activation and before T cell exhaustion, a window that is likely closed in most patients. However, by first jump-starting the T cell response using an oncolytic virus, the anti-tumor activity of ENT and PD1 blockade is restored. These data establish a general paradigm, independent of tumor type, to rationally manipulate anti-tumor immunity.