Siglec-6 is a target for chimeric antigen receptor T-cell treatment of chronic lymphocytic leukemia

• Published in: Leukemia Vol. 35; no. 9; pp. 2581 - 2591
• Main Authors: Kovalovsky, Damian, Yoon, Jeong Heon, Cyr, Matthew G., Simon, Samantha, Voynova, Elisaveta, Rader, Christoph, Wiestner, Adrian, Alejo, Julie, Pittaluga, Stefania, Gress, Ronald E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2021; Nature Publishing Group
• Subjects: 13/21; 13/31; 13/51; 42/109; 59/5; 631/250/251; 631/67/1990/283/1895; 64/60; Antibodies; Antigens; Cancer Research; Care and treatment; CD19 antigen; Cell receptors; Cell therapy; Cellular therapy; Chimeric antigen receptors; Chronic lymphocytic leukemia; Critical Care Medicine; Development and progression; Genetic aspects; Health aspects; Hematology; Hematopoietic stem cells; Immune system; Immunotherapy; Intensive; Internal Medicine; Leukemia; Lymphatic leukemia; Lymphocytes; Lymphocytes T; Medicine; Medicine & Public Health; Methods; mRNA; Oncology; Patient outcomes; Placenta; Receptors; Stem cell transplantation; Stem cells; Xenografts; Xenotransplantation; United States
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/s41375-021-01188-3

The only current curative treatment for chronic lymphocytic leukemia (CLL) is allogenic hematopoietic stem cell transplantation. Chimeric antigen receptor treatment targeting CD19 for CLL achieved some complete responses, suggesting the need for alternative or combinational therapies to achieve a more robust response. In this work, we evaluated CAR-T cells specific for Siglec-6, an antigen expressed in CLL, as a novel CAR-T cell treatment for CLL. We found that detection of SIGLEC6 mRNA and Siglec-6 protein is highly restricted to placenta and immune cells in other tissues and it is not expressed in hematopoietic stem cells. We generated CAR-T cells specific for Siglec-6 based on the sequence of the fully human anti-Siglec-6 antibody (JML1), which was identified in a CLL patient that was cured after allo-hematopoietic stem cell transplantation (alloHSCT), and observed that it specifically targeted CLL cells in vitro and in a xenograft mouse model. Interestingly, a short hinge region increased the activity of CAR-T cells to target cells expressing higher Siglec-6 levels but similarly targeted CLL cells expressing lower Siglec-6 levels in vitro and in vivo. Our results identify a novel CAR-T cell therapy for CLL and establish Siglec-6 as a possible target for immunotherapy.