Enhancing the cytotoxicity of T cells in NRAS; ASXL1-AML through combined inhibition of MEK and HDACs

Acute myeloid leukemia (AML) is a malignant blood cancer that mainly occurs in the elderly. AML is highly heterogeneous, and its treatment outcome is greatly influenced by the leukemia-driving mutations. Oncogenic NRAS mutations not only associate with AML progression, but more importantly link to generation of multiple drug resistance and treatment failure in AML. Therefore, novel therapeutic regimens targeting oncogenic NRAS represent an unmet clinical need. We recently developed an animal model of NRAS-driven AML. Through a re-purpose drug screen using these AML cells, we have identified that a novel combination of two drugs, both of which have established safety profiles in human beings, potently suppressed AML progression in immunocompetent animals but not in immunodeficient animals. Further in-depth analysis revealed that the combo treatment not only directly killed AML cells but more importantly enhanced the anti-leukemia killing of T cells. We speculate that the combo drug treatment may upregulate tumor-specific antigen presentation on leukemia cells, thus enhancing the leukemia recognition of T cells. In addition, the combo drug may preserve leukemia-recognizing T cells in activated but not exhausted or dysfunctional status. In this proposal, we will evaluate our idea in leukemia and T cell co-cultures and in AML mice. We would also try to isolate the specific group of T cells that are responsible for leukemia cell killing. Moreover, we will determine if we can achieve similar effects in animals xenografted with human AML cells and their HLA-matching T cells. The success of our proposal will not only provide fundamental insights in anti-AML immunity but could also potentially lead to potent and efficacious novel immunotherapies for treating drug-resistant/relapsed NRAS-driven AML or other myeloid leukemias.