Jetani H, Navarro-Bailón A, Maucher M, et al. Siglec-6 Is a Novel Target for CAR T-Cell Therapy in Acute Myeloid Leukemia (AML). Blood. 2021; (doi: 10.1182/blood.2020009192).
Treatment with sialic-acid-binding immunoglobulin-like lectin (Siglec)-6-specific chimeric antigen receptor (CAR) T cells eliminated primary acute myeloid leukemia (AML) blasts and led to complete remission from the disease in a xenograft model in mice, according to new research. Using a Siglec-6-specific CAR with a targeting domain derived from the JML-1 human monoclonal antibody, researchers determined that Siglec-6 is primarily expressed on AML cell lines and primary AML blasts, including AML stem cells. In pre-clinical models, Siglec-6-CAR T-cell therapy generates anti-leukemia reactivity that correlates with Siglec-6-expression, including inducing complete remission in a xenograft AML model with immunodeficient mice. The research noted Siglec-6-expression on transformed B-cells in chronic lymphocytic leukemia (CLL) and specific anti-CLL-reactivity of Siglec-6-CAR T-cells <="" i="">. Normal hematopoietic stem and progenitor cells (HSC/P) were negative for Siglec-6 and not affected by Siglec-6-CAR T-cells in pre-clinical analyses. Siglec-6 was detected in a proportion of memory (and naïve) B-cells and basophilic granulocytes in mature normal hematopoietic cells, indicating potential for possible on-target/off-tumor reactivity. The researchers note the lack of expression of Siglec-6 on normal HSC/P is a major difference from others in the Siglec family and other CAR target antigens currently being studied for AML.