Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia

Jetani H, Navarro-Bailón A, Maucher M, Frenz S, Verbruggen C, Yeguas A, Vidriales MB, González M, Rial Saborido J, Kraus S, Mestermann K, Thomas S, Bonig H, Luu M, Monjezi R, Mougiakakos D, Sauer M, Einsele H, Hudecek M (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Blood American Society of Hematology

Book Volume: 138

Pages Range: 1830-1842

Journal Issue: 19

DOI: 10.1182/blood.2020009192

Abstract

Acute myeloid leukemia (AML) is an attractive entity for the development of chimeric antigen receptor (CAR) T-cell immunotherapy because AML blasts are susceptible to T-cell–mediated elimination. Here, we introduce sialic acid–binding immunoglobulin-like lectin 6 (Siglec-6) as a novel target for CAR T cells in AML. We designed a Siglec-6–specific CAR with a targeting domain derived from the human monoclonal antibody JML-1. We found that Siglec-6 is commonly expressed on AML cell lines and primary AML blasts, including the subpopulation of AML stem cells. Treatment with Siglec-6 CAR T cells confers specific antileukemia reactivity that correlates with Siglec-6 expression in preclinical models, including induction of complete remission in a xenograft AML model in immunodeficient mice (NSG/U937). In addition, we confirmed Siglec-6 expression on transformed B cells in chronic lymphocytic leukemia (CLL), and specific anti-CLL reactivity of Siglec-6 CAR T cells in vitro. Of particular interest, we found that Siglec-6 is not detectable on normal hematopoietic stem and progenitor cells (HSPCs) and that treatment with Siglec-6 CAR T cells does not affect their viability and lineage differentiation in colony-formation assays. These data suggest that Siglec-6 CAR T-cell therapy may be used to effectively treat AML without the need for subsequent allogeneic hematopoietic stem cell transplantation. In mature normal hematopoietic cells, we detected Siglec-6 in a proportion of memory (and naïve) B cells and basophilic granulocytes, suggesting the potential for limited on-target/off-tumor reactivity. The lack of expression of Siglec-6 on normal HSPCs is a key to differentiating it from other Siglec family members (eg, Siglec-3 [CD33]) and other CAR target antigens (eg, CD123) that are under investigation in AML, and it warrants the clinical investigation of Siglec-6 CAR T-cell therapy.

Authors with CRIS profile

Judit Rial Saborido Medizinische Fakultät Dimitrios Mougiakakos Medizinische Fakultät

Involved external institutions

Universitätsklinikum Würzburg DE Germany (DE) Julius-Maximilians-Universität Würzburg DE Germany (DE) Complejo Hospitalario de Salamanca / Complejo Asistencial Universitario de Salamanca ES Spain (ES) Universitätsklinikum Regensburg DE Germany (DE) Goethe-Universität Frankfurt am Main DE Germany (DE)

How to cite

APA:

Jetani, H., Navarro-Bailón, A., Maucher, M., Frenz, S., Verbruggen, C., Yeguas, A.,... Hudecek, M. (2021). Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia. Blood, 138(19), 1830-1842. https://doi.org/10.1182/blood.2020009192

MLA:

Jetani, Hardikkumar, et al. "Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia." Blood 138.19 (2021): 1830-1842.

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