基于配体靶向 c-kit 的工程化 γδ T 细胞治疗急性髓系白血病策略

The application of immunotherapies such as chimeric antigen receptor (CAR) T therapy or bi-specific 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 T cells as a cytotoxic alternative to 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 T cells permits its use as an allogeneic, off-the-shelf therapeutic. To this end, we show mSCF CAR- and hSCF sBite-modified 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 T cells moderately extend survival of NSG mice engrafted with disseminated AML, but therapeutic efficacy is limited by lack of T-cell homing to murine bone marrow.

Together, these data demonstrate preclinical efficacy and support further investigation of SCF-based T-cell therapeutics for the treatment of myeloid malignancies.