Siglec-6 is a novel target for CAR T-cell therapy in acute myeloid leukemia.
Hardikkumar JetaniAlmudena Navarro-BailónMarius MaucherSilke FrenzChristina VerbruggenAna YeguasMaria Vidriales VicenteMarcos González-DíazJudit Rial SaboridoSabrina KrausKatrin MestermannSimone ThomasHalvard BonigMaik LuuRazieh MonjeziDimitrios MougiakakosMarkus SauerHermann EinseleMichael HudecekPublished in: Blood (2021)
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.
Keyphrases
- acute myeloid leukemia
- cell therapy
- allogeneic hematopoietic stem cell transplantation
- stem cells
- poor prognosis
- chronic lymphocytic leukemia
- acute lymphoblastic leukemia
- mesenchymal stem cells
- signaling pathway
- endothelial cells
- high throughput
- drug delivery
- computed tomography
- immune response
- bone marrow
- binding protein
- deep learning
- cell proliferation
- long non coding rna
- big data
- skeletal muscle
- data analysis
- human health