BET inhibitors synergize with anti-PD1 in rescuing T cell exhaustion in acute myeloid leukemia by increasing TCF1 expression

Abstract

Abstract Acute myeloid leukemia (AML) is an aggressive myeloid lineage white blood cell cancer with an extremely poor prognosis that occurs most frequently above 60 years of age. The current standard of care consists of an intensive induction chemotherapy regimen. Many patients cannot withstand this intensive treatment regimen and rely on other targeted therapies such as small-molecule inhibitors, which inhibit specific oncogenic proteins, but these are not durable. Immunotherapies, which block stimuli that inhibit T cell functions, have had great success in achieving durable remissions in metastatic melanoma. Studies have shown that AML patients exhibit markers of immune suppression by the tumor microenvironment such as increased levels of PD1/LAG3+ exhausted T cells as well as regulatory T cells and myeloid-derived suppressor cells. In addition, inhibitors targeting the BET proteins family, which are histone readers, potently target leukemia cells by reducing myc but also increase IFNy and IL-2 production in T cells by inhibiting BATF, a negative regulator of TCF1. TCF1 is a critical factor in effector memory T cells and TCF1+ T cells are the primary expanders with aPD1. We therefore hypothesized that BETi and aPD1 would synergize in treating AML by modulating both tumor intrinsic and extrinsic factors (enhanced T cell activity). T cells derived from an immune competent FLT3-ITD/TET2/Lys-Cre AML mouse model show significant proliferative dysfunction and enhanced exhaustion markers, but are rescued by ex vivo treatment with BETi + aPD1. Further, In vivo treatment with this novel drug combination showed enhanced reduction of leukemic blasts, increased T cell proliferation, and in vitro expansion of TCF1+ effector memory CD8 T cells.