Immune modulating potential of novel CKIɑ and CDK7/9 inhibitors in AML mouse model

Acute Myeloid Leukemia (AML) is an aggressive hematologic malignancy. In the past decades, there were few advancements in standard AML therapies. New therapies are highly in demand. A51, a small molecule multi-kinase inhibitor targeting CKIɑ and CDK7/9, has shown a great anti-leukemic effect in pre-clinical AML models. A51 treatment significantly prolongs the life span of the mice inoculated with AML cells and leads to ~ 40% cure from leukemia. However, in this study, we found that these therapeutic effects are highly dependent on an intact immune system. In the immunodeficient RAG mice, or T cells depleted mice, A51-induced leukemia cure was completely diminished. On the other hand, we characterized a T cell-dependent, tumor-type-specific anti-leukemia immune memory in the mice rescued by A51. Over 70% of the rescued mice can survive the challenge by the inoculation of the same type of AML by its own immune system. Although how A51 potentiates this immune memory is not immediately clear. Some preliminary results revealed an unexpected direction, A51 can also induce Gesdermin E cleavage and cause pyroptosis, an inflammatory cell death, in murine and human AML cells. This newly discovered feature of A51 might be a good clue to reveal the involvement of the immune system in A51 therapeutic effect. With a better understanding of the underlying relationship of immune system and AML therapy such as A51 treatment, we might be able to promote antitumor immunity and optimize the curative effect of clinical AML therapies.