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

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• Bispecific antibodies (BsAbs) targeting CD33 show promise for relapsed/refractory acute myeloid leukemia (AML).
• Clinical trials indicate a need for improved durable responses in AML treatment.
• Activation of the innate immune system via stimulator of interferon genes (STING) is a potential therapeutic avenue.

Purpose of the Study:

• To investigate if STING activation can enhance the efficacy of a CD33-targeting BsAb (AMG 330) against AML.
• To elucidate the mechanisms underlying the synergistic effects of STING agonists and AMG 330.
• To explore the potential of combining STING agonists with CD33-targeting BsAbs for improved AML therapy.

Main Methods:

• In vitro cytotoxicity assays using AML cell lines and primary AML cells.
• Transcriptomic analyses and CRISPR-Cas9 knockout screens to identify molecular mechanisms.
• Immunoblotting to assess protein level changes.
• In vivo studies using a xenograft AML model.

Main Results:

• STING agonists (cGAMP, diABZI) significantly enhanced AMG 330-mediated cytotoxicity against AML cells.
• Synergistic effects were observed in both AML cell lines and primary patient cells.
• Activated T cells, through IFN-γ and TNF, increased AML cell susceptibility to STING activation.
• STING activation led to enhanced type I IFN production and IFN-stimulated gene induction, creating a positive feedback loop with T cells.

Conclusions:

• Combining STING agonists with CD33-targeting BsAbs represents a potent strategy to enhance anti-AML immune responses.
• IFN-γ plays a critical role in mediating both BsAb efficacy and STING pathway activation in AML.
• This combination therapy holds promise for overcoming limitations of current BsAb treatments in AML.