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

Kovalovsky, Damián; Yoon, Jeong Heon; Cyr, Matthew; Simon, Samantha; Voynova, Elisaveta; Rader, Christoph; Wiestner, Adrian; Alejo, Julie; Pittaluga, Stefania; Gress, Ronald E.

doi:10.1038/s41375-021-01188-3

Cited by 18 publications

(24 citation statements)

References 25 publications

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“…[41][42][43] A predicted advantage of targeting Siglec-6 rather than CD19 in CLL is that it is less toxic to normal B cells. While this article was being revised, a study by Kovalovsky et al 44 demonstrated efficacy of Siglec-6 CAR T cells against CLL cells in vitro and MEC-1 CLL cells overexpressing the Siglec-6 target antigen in vivo.…”

Section: Discussionmentioning

confidence: 99%

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

Jetani

Navarro‐Bailón

Maucher

et al. 2021

Blood

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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.

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Section: Discussionmentioning

confidence: 99%

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

Jetani

Navarro‐Bailón

Maucher

et al. 2021

Blood

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“…CAR-T cells targeting Siglec-6 and CD23 separately have been developed, and their effects will be confirmed in future experiments [ 136 , 137 ].…”

Section: Haematologic Cancersmentioning

confidence: 99%

Tumor buster - where will the CAR-T cell therapy ‘missile’ go?

Zhang

Cao

et al. 2022

Mol Cancer

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Chimeric antigen receptor (CAR) T cell (CAR-T cell) therapy based on gene editing technology represents a significant breakthrough in personalized immunotherapy for human cancer. This strategy uses genetic modification to enable T cells to target tumor-specific antigens, attack specific cancer cells, and bypass tumor cell apoptosis avoidance mechanisms to some extent. This method has been extensively used to treat hematologic diseases, but the therapeutic effect in solid tumors is not ideal. Tumor antigen escape, treatment-related toxicity, and the immunosuppressive tumor microenvironment (TME) limit their use of it. Target selection is the most critical aspect in determining the prognosis of patients receiving this treatment. This review provides a comprehensive summary of all therapeutic targets used in the clinic or shown promising potential. We summarize CAR-T cell therapies’ clinical trials, applications, research frontiers, and limitations in treating different cancers. We also explore coping strategies when encountering sub-optimal tumor-associated antigens (TAA) or TAA loss. Moreover, the importance of CAR-T cell therapy in cancer immunotherapy is emphasized.

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“…Additionally, Siglec-6 expression has been reported in AML blasts and B cells in subjects with chronic lymphocytic leukemia (CLL) [ 34 ] and mucosa-associated lymphoid tissue lymphoma [ 35 ]. As Siglec-6 mRNA and protein are not expressed in hematopoietic stem cells, they are novel targets for CAR-T-cell immunotherapy in CLL [ 20 , 23 ].…”

Section: Expression Spectrum Of Siglecs In Tumorsmentioning

confidence: 99%

“…Siglec-6 is broadly expressed in CLL and warrants investigation as a candidate target for antibody-based immunotherapeutic interventions [ 83 ]. Recent research generated a fully human-derived anti-Siglec-6 CAR and showed that it effectively eliminated CLL cells in vitro and in xenograft models [ 23 ]. In conclusion, Siglec-6 is a possible target for CLL immunotherapy.…”

Section: Targeting Siglecs In Tumor Therapymentioning

confidence: 99%

The intriguing roles of Siglec family members in the tumor microenvironment

Jiang

Kang³

et al. 2022

Biomark Res

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Sialic acid-binding receptors are expressed on the surfaces of a variety of immune cells and have complex and diverse immunoregulatory functions in health and diseases. Recent studies have shown that Siglecs could play diverse immune and nonimmune regulatory roles in the tumor microenvironment (TME) and participate in tumor progression through various mechanisms, such as regulating tumor growth and metastasis, mediating the inflammatory response, and promoting tumor immune escape, thereby affecting the prognoses and outcomes of patients. However, depending on the cell type in which they are expressed, each Siglec member binds to corresponding ligands in the microenvironment milieu to drive diverse cell physiological and pathological processes in tumors. Therefore, we herein summarize the expression spectra and functions of the Siglec family in human diseases, particularly cancer, and highlight the possibility of therapeutic interventions targeting the TME in the future.

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

Cited by 18 publications

References 25 publications

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

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

Tumor buster - where will the CAR-T cell therapy ‘missile’ go?

The intriguing roles of Siglec family members in the tumor microenvironment

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