Combining STING agonism and T-cell-based therapy against AML

• Applicant: Dr. Daniel Nixdorf, Ph.D.
• Subject Area: Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 566435897

Despite advancements in the treatment of acute myeloid leukemia (AML), the outcomes remain poor, with allogeneic stem cell transplantation being the most effective option, however limited to a subset of patients. T-cell-based therapies, like chimeric antigen receptor (CAR) T cells and bispecific T-cell-engagers (TCE), have shown promising results in B-cell malignancies but face challenges in AML, including target heterogeneity, therapy-related toxicities, and T-cell exhaustion. In addition, the immunosuppressive tumor microenvironment (TME) in AML, characterized by inhibitory receptors, regulatory cells, and impaired T-cell function, further hampers the efficacy of T-cell immunotherapies. Overcoming these barriers is crucial for improving AML treatment outcomes. Strategies to remodel the TME and to engage additional cells of the innate and adaptive immune system seem promising. We have recently discovered that extrinsic activation of the cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway strongly potentiates the efficacy of T-cell-based immunotherapy of AML. We discovered functional IFNy- and STING- signaling as crucial components mediating a forward-feedback cross-talk between T cells and target AML cells leading to a pronounced cytotoxic T-cell phenotype. We want to pursue this further by exploring the molecular cascades involved in these processes (Objective I), particularly using an unbiased genome-wide CRISPR-Cas9 screen in AML. Next, we want to broaden our understanding beyond the mere interplay of AML target cells and human T cells towards a more holistic context, by additionally assessing the effects on, and by other immune cells (Objective II). This will be addressed using innovative in vitro co-culture assays of AML-, T-, NK-cells, DCs, monocytes and macrophages, as well as RNA-sequencing. Additionally, cutting edge iPSC-derived 3D-bone marrow organoids will be used to more closely mimic the bone marrow TME. High-resolution confocal microscopy will be used to analyze organoid infiltration of primary AML cells and T cells. Lastly (Objective III), we want to investigate the efficacy of the combination therapy in a clinically relevant humanized AML mouse model. The influence of the innate and adaptive immune system will be analyzed by multi-parameter-flow cytometry (MPFC). Single cell RNA profiling of bone marrow samples will shed light on the transcriptional changes within the AML-TME. Additionally, these data will inform on potential toxicities including the risk of cytokine release syndrome of the combined use of STING agonists and T-cell-based therapy in AML. Our study may thus open new possibilities to improve T-cell-based immunotherapy of AML.

• DFG Programme: Research Grants