Multi-omics analysis reveals CLEC2A is a leukemia-restricted CART target in KMT2A-rearranged Acute Myeloid Leukemia

Outcomes for patients with acute myeloid leukemia (AML) remain unsatisfactory despite intensive chemotherapy and consolidative hematopoietic stem cell transplant. ^1-3 Targeted therapies, such as FLT3 inhibitors ^4,5 and gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate, ^6,7 have demonstrated the ability to augment anti-leukemia responses, however patients with high-risk cyto-molecular alterations continue to have high rates of relapse. ^2,3 With the success of adoptive cellular therapies including chimeric antigen receptor T (CART) cells in lymphoid malignancies ^8-10 , there has been tremendous efforts to develop AML-targeting immunotherapies with nearly all approaches directed against shared antigens found on both AML blasts and normal myeloid cells, which poses significant risk for myeloablation limiting their use solely as a bridge to transplant. ^11,12 Here we show a multi-omics target discovery approach identifying CLEC2A as a leukemia-restricted target enriched in high-risk KMT2A-rearranged AML without expression in normal hematopoietic cells or virtually all tissues in the body. CLEC2A expression is directly associated with the leukemia-driving KMT2A fusion oncoprotein allowing us to exploit this dependency in KMT2A-rearranged AML. We developed and validated first-in-class human CLEC2A binders, which were reformatted to generate CLEC2A-targeting CART cells that demonstrate robust anti-leukemia efficacy, improving survival with durable persistence in immune-deficient human AML xenograft murine models. CLEC2A-targeting CART cells provide one of the first leukemia-restricted immunotherapeutic approaches for high-risk AML with the potential to improve outcomes without risk for myeloablation supporting translation of CLEC2A-targeting CART cells to clinical trial.