A novel CD123xVδ2 bispecific T cell engager induces potent and tumor selective Vγ9Vδ2-T cell activity against CD123 expressing acute myeloid leukemia and myelodysplastic syndrome.

Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) have poor outcomes. We developed a humanized, half-life-extended CD123 × Vδ2 bispecific T-cell engager (bsTCE) to redirect Vγ9Vδ2 T cells to CD123-expressing malignancies. The engager bound selectively to Vγ9Vδ2 T cells and CD123-positive AML cells, with no detectable off-target interactions in specificity and tissue cross-reactivity assays. In vitro, it induced potent lysis of tumor cell lines and patient-derived AML and MDS cells, including at low effector-to-target cell ratios, supportive of serial killing. Compared with a CD123 × CD3 bsTCE, it induced lower levels of cytokines associated with cytokine release syndrome. Vγ9Vδ2-T cells preferentially lysed tumor cells over CD123-positive non-malignant cells, including plasmacytoid dendritic cells, and were detectable in patients' peripheral blood and bone marrow. The engager reduced tumor growth in an AML xenograft model and showed antibody-like pharmacokinetics in nonhuman primates. A phase 1 clinical trial was initiated (ACTRN12624001214527).