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

  1. Navarro-Bailón, Almudena 1
  2. Vidriales, María-Belén 2
  3. Kraus, Sabrina 3
  4. Mestermann, Katrin 4
  5. Sauer, Markus 5
  6. Hudecek, Michael 4
  7. Verbruggen, Christina Mathilde 6
  8. Rial Saborido, Judit 7
  9. Thomas, Simone 8
  10. Jetani, Hardikkumar 4
  11. Luu, Maik 4
  12. Maucher, Marius 4
  13. Frenz, Silke 4
  14. Bonig, Halvard 9
  15. González, Marcos 10
  16. Mougiakakos, Dimitrios 11
  17. Yeguas, Ana 12
  18. Einsele, Hermann 13
  19. Monjezi, Razieh 14
  1. 1 Universitaetsklinikum Wuerzburg, Germany
  2. 2 University Hospital of Salamanca (HUS/IBSAL), CIBERONC- CB16/12/00233 and Center for Cancer Research-IBMCC (USAL-CSIC), Salamanca, Spain
  3. 3 Uniklinikum Würzburg, Würzburg, Germany
  4. 4 Universitaetsklinikum Wuerzburg, Wuerzburg, Germany
  5. 5 University of Wuerzburg, Wuerzburg, Germany
  6. 6 University of Würzburg, Wuerzburg, Germany
  7. 7 Universitätsklinikum Erlangen-Nürnberg, Erlangen, Germany
  8. 8 Regensburg Center for Interventional Immunology, University of Regensburg, Germany
  9. 9 Institut für Transfusionsmedizin und Immunhämatologie, Goethe Universität Frankfurt, Germany
  10. 10 Hospital Universitario de Salamanca, Salamanca, Spain
  11. 11 University of Erlangen-Nuremberg, Erlangen, Germany
  12. 12 Department of Hematology, University Hospital of Salamanca (HUS/IBSAL), CIBERONC- CB16/12/00233 and Center for Cancer Research-IBMCC (USAL-CSIC), Salamanca, Spain
  13. 13 Universitätsklinikum Würzburg, Würzburg, Germany
  14. 14 Universitaetsklinikum Wuerzburg
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Revista:
Blood

ISSN: 0006-4971,  1528-0020

Año de publicación: 2021

Tipo: Artículo

DOI: 10.1182/BLOOD.2020009192 GOOGLE SCHOLAR

Otras publicaciones en: Blood

Resumen

Acute myeloid leukemia (AML) is attractive for the development of CAR T-cell immunotherapy because AML blasts are susceptible to T-cell-mediated elimination. Here, we introduce sialic-acid-binding immunoglobulin-like lectin (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 a human monoclonal antibody JML‑1. We found that Siglec-6 is prevalently 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 anti-leukemia reactivity that correlates with Siglec-6-expression in pre-clinical 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 show 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 (HSC/P) 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 a 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 lacking expression of Siglec-6 on normal HSC/P is a key differentiator from other Siglec-family members (e.g. Siglec-3=CD33) and other CAR target antigens, e.g. CD123, that are under investigation in AML and warrants the clinical investigation of Siglec-6-CAR T-cell therapy.