Ligand-based targeting of c-kit using engineered γδ T cells as a strategy for treating acute myeloid leukemia

Ligand-based targeting of c-kit using engineered γδ T cells as a strategy for treating acute myeloid leukemia

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The application of immunotherapies such as chimeric antigen receptor (CAR) T therapy or bi-specific click here T cell engager (BiTE) therapy to manage myeloid malignancies has proven more challenging than for B-cell malignancies.This is attributed to a shortage of leukemia-specific cell-surface antigens that distinguish healthy from malignant myeloid populations, and the inability to manage myeloid depletion unlike B-cell aplasia.Therefore, the development of targeted therapeutics for myeloid malignancies, such as acute myeloid leukemia (AML), requires new approaches.Herein, we developed a ligand-based CAR and secreted bi-specific T cell engager (sBite) to target c-kit using its cognate ligand, stem cell factor (SCF).

c-kit is highly expressed on AML blasts and correlates with resistance to chemotherapy and poor prognosis, making it an ideal candidate for which to develop targeted therapeutics.We utilize γδ T cells as a cytotoxic alternative to αβ T cells and a transient transfection system as both a safety precaution and switch to remove alloreactive modified cells that may hinder successful transplant.Additionally, the use of γδ T cells permits its use as an allogeneic, off-the-shelf therapeutic.To this end, we show mSCF CAR- and hSCF sBite-modified γδ T cells are proficient in killing c-kit+ AML cell lines and sca-1+ murine bone marrow cells in vitro.

In vivo, hSCF sBite-modified γδ T cells moderately extend survival of NSG mice engrafted with disseminated AML, but therapeutic efficacy is limited by lack of γδ T-cell homing to murine bone marrow.Together, these data demonstrate preclinical efficacy Neuw Rebel Skinny Eternal Black Jeans and support further investigation of SCF-based γδ T-cell therapeutics for the treatment of myeloid malignancies.