STING activation improves T-cell-engaging immunotherapy for acute myeloid leukemia

T-cell-recruiting bispecific antibodies (BsAbs) are in clinical development for relapsed/refractory acute myeloid leukemia (AML). Despite promising results, early clinical trials have failed to demonstrate durable responses. We investigated whether activation of the innate immune system through stimulator of interferon (IFN) genes (STING) can enhance target cell killing by a BsAb targeting CD33 (CD33 bispecific T-cell engager molecule; AMG 330). Indeed, we show that cytotoxicity against AML mediated by AMG 330 can be greatly enhanced when combined with the STING agonist 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) or diamidobenzimidazole (diABZI). We used in vitro cytotoxicity assays, immunoblotting, transcriptomic analyses, and extensive CRISPR-Cas9 knockout experiments to investigate the enhancing effect of a STING agonist on the cytotoxicity of AMG 330 against AML. Importantly, we validated our findings with primary AML cells and in a xenograft AML model. Mechanistically, in addition to direct cytotoxic effects of STING activation on AML cells, activated T cells render AML cells more susceptible to STING activation through their effector cytokines, IFN-

• Linder, A.
• Nixdorf, D.
• Kuhl, N.
• Piseddu, I.
• Xu, T.
• Holtermann, A. V.
• Kuut, G.
• Endres, R.
• Philipp, N.
• Bücklein, V.
• de Graaff, J.
• Carell, T.
• Kobold, S.
• Kischel, R.
• Hornung, V.
• Subklewe, M.