Immune correlates of TP53 mutational status in acute myeloid leukemia

Tumor phenotypes are dictated not only by the neoplastic cell component, but also by the tumor microenvironment (TME), which is inherently immuno-suppressive, is equipped to hamper effector T-cell function and includes immune and inflammatory cells, soluble mediators such as interferon (IFN)-gamma and extracellular matrix components. Acute myeloid leukemia (AML) is characterized by clonal expansion of poorly differentiated myeloid precursors, resulting in impaired hematopoiesis and often bone marrow (BM) failure. TP53 mutations occur in 8-10% of de novo AML and are associated with chemotherapy refractoriness and with poor prognostic features. Our multi-institutional study was undertaken to characterize the immune ecosystem of non-promyelocytic AML with TP53 mutations using the nCounter™ system (NanoString Technologies Inc., Seattle, WA), with the ultimate goal to implement new immunotherapy agents for patients harboring this molecularly defined subtype of AML. We detected high T-cell infiltration and high expression of immune checkpoints and IFN- signaling molecules in patients with TP53 mutated AML compared with AML subgroups with other risk-defining molecular lesions. We also computed an experimentally derived, TP53-related immune gene signature which stratified survival in a broad cohort of TCGA AML cases. Finally, our correlative analyses in patients with relapsed/refractory AML treated with flotetuzumab, an investigational, bispecific CD123×CD3 DART® molecule, showed therapeutic efficacy in individuals with altered TP53 status and identified immune gene signatures that support the prediction of clinical responses. In conclusion, our study has identified unique immunological profiles in patients with TP53 mutated AML. From a clinical standpoint, ‘immune enriched’ AMLs might be amenable to immunotherapy approaches with T-cell engagers.

Learning Objectives:

1. Learn about unique immunological profiles of patients with acute myeloid leukemia (AML)

2. Explore protein signatures and how they influence immunotherapy treatment choices

3. Learn how digital spatial profiling is impacting the field of oncology