Identification of Siglec-15 as a novel target for CAR-T cell therapy in acute myeloid leukemia

Chimeric antigen receptor (CAR)-modified T cells have demonstrated notable success in treating B-cell malignancies. However, applying CAR T-cell therapy to acute myeloid leukemia (AML) poses considerable challenges, primarily due to the extensive phenotypic heterogeneity and target restriction among different AML subtypes. Therefore, it is crucial to increase the diversity of target antigens for CAR T-cell therapy in AML. In this study, we have identified Siglec-15, a sialic acid-binding immunoglobulin-like lectin, as a novel and promising target for CAR T-cell therapy in AML. Siglec-15 is a transmembrane protein that is extensively expressed in primary AML blasts and AML cell lines, including a subpopulation of AML stem cells. It is also expressed to a limited extent in hematopoietic stem and progenitor cells (HSPCs), as well as in mature T and B cells. Preclinical models have demonstrated that co-culturing anti-Siglec-15 CAR T cells with U937 or Molm13 cells triggers specific anti-leukemic activity in vitro, and administering these CAR T cells has also led to remission in a U937 xenograft model with B-NSG mice. In conclusion, we have developed a novel therapeutic approach for AML utilizing anti-Siglec-15 CAR T cells that effectively target leukemic cells while preserving normal hematopoiesis.