Expanding the Therapeutic Potential of CLEC2A CAR T cells for Acute Myeloid Leukemia

Acute myeloid leukemia (AML) remains difficult to treat with high rates of relapse and poor overall survival. One high-risk subtype of AML, KMT2A-rearranged AML, is highly prevalent in childhood and therapy-related AML and comprises one of the most refractory and fatal leukemias regardless of age. Current conventional chemotherapy has failed to adequately treat these high-risk subtypes of AML highlighting the need for innovative treatments to improve the current dismal outcomes. Cellular immunotherapies, such as chimeric antigen receptor (CAR) T cells, target a specific marker on the outside of cancer cells directing the immune system to kill the cancer cells. CAR T cells have revolutionized treatment of B-cell blood cancers, but this same success has not been achieved in AML. The critical limiting step to effective therapy in AML is the lack of appropriate targeted therapies. Nearly all immunotherapies for AML target shared markers expressed on both leukemia cells and normal blood cells posing significant risk for toxicity with limited success seen to date. Through the largest therapeutic target discovery effort in pediatric AML, we identified CLEC2A to be highly expressed on leukemia cells in patients with high-risk AML with no expression in normal blood cells and virtually absent in all normal tissues in the body making it an ideal therapeutic target. We have generated the first ever CLEC2A-targeting CAR T cells which have shown remarkable responses and significantly improved survival against KMT2A-rearranged AML preclinical models. We are now primed to expand the therapeutic potential of targeting CLEC2A with CAR T cells for patients with other high-risk subtypes of AML including AML that has developed outside of the bone marrow and identify the potential impact of prior chemotherapy treatment on CAR T cell response. Our proposed work will support moving CLEC2A CAR T cells into clinical trial, providing one of the first leukemia-specific targeted therapies for patients with AML. Our work evaluating the impact of prior chemotherapy treatment on CAR T responses will extend beyond CLEC2A-targeting therapies and provide invaluable insight into the burgeoning field of CAR T cell therapy to treat AML.