Jetani, Hardikkumar and Navarro-Bailon, Almudena and Maucher, Marius and Frenz, Silke and Verbruggen, Christina and Yeguas, Ana and Vidriales, Maria Belen and Gonzalez, Marcos and Saborido, Judit Rial and Kraus, Sabrina and Mestermann, Katrin and Thomas, Simone and Bonig, Halvard and Luu, Maik and Monjezi, Razieh and Mougiakakos, Dimitrios and Sauer, Markus and Einsele, Hermann and Hudecek, Michael (2021) Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia. BLOOD, 138 (19). pp. 1830-1842. ISSN 0006-4971, 1528-0020
Full text not available from this repository. (Request a copy)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 CART 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 naive) 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | B-CELL; ANTIGEN; CD19; EXPRESSION; REMISSIONS; MATURATION; EFFICACY; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 16 Sep 2022 06:38 |
| Last Modified: | 16 Sep 2022 06:38 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47500 |
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