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Ligand-based CAR and secreted bi-specific T cell engager targeting c-kit for the treatment of AML

Branella GM, Lee JY, Okalova J, et al. Ligand-Based Targeting of C-Kit Using Engineered γδ T Cells as a Strategy for Treating Acute Myeloid Leukemia. Frontiers in Immunology. 2023; (doi: 10.3389/fimmu.2023.1294555).

In pursuit of effective treatments for acute myeloid leukemia (AML) and other myeloid malignancies, which have had less success with adoptive cell therapy (ACT) than B-cell malignancies, scientists are training their focus on CD117 (c-kit). In the absence of known leukemia-specific, cell-surface antigens that differentiate between healthy and malignant myeloid cells, c-kit expression is an apt alternative. It is observed in the vast majority of AML patients and associated with poor prognosis and resistance to chemotherapy. The study authors report the development of a ligand-based chimeric antigen receptor (CAR) and a secreted bi-specific T cell engager (sBite) to target c-kit using its cognate ligand, stem cell factor (SCF). In vitro, mSCF CAR- and hSCF sBite-modified γδ T cells demonstrated killing proficiency against c-kit+ AML cell lines, ablating >90% of AML cell lines during a short-term cytotoxicity assay at a low effector-to-target ratio. The findings lay the groundwork for further investigation into the use of ligand-based γδ T-cell therapies for the treatment of myeloid malignancies.

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