MAY 20, 2020 11:45 AM EDT | APAC MAY 21, 2020 2:45 PM CST

Immune Infiltration Correlates of TP53 Mutational Status in Acute Myeloid Leukemia

Speaker
  • Professor of Cancer Immunotherapy, John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University
    Biography
      Sergio Rutella, MD PhD, is a licensed hematologist and Fellow of the Royal College of Pathologists with a long-standing interest in leukemia immunobiology and immunotherapy. Sergio is currently the Professor of Cancer Immunotherapy at Nottingham Trent University, United Kingdom. His research focuses on visualizing the state of cancer-immune interactions in patients with acute leukemia, on immune biomarker discovery and on therapeutic strategies to revert cancer-induced immune suppression with the aim to guide treatment choices and improve clinical outcome.

    Abstract

    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)-g 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 poor prognostic features. The development and delivery of new therapeutic strategies for high-risk AML, including immunotherapy, therefore remains a priority.

    Our multi-institutional study was undertaken to characterize the immune ecosystem of non-promyelocytic AML with TP53 mutations using he nCounter™ system (NanoString Technologies Inc., Seattle, WA), with the ultimate goal to implement new immunotherapy agents for patients with specific immunologic subtypes of AML.

    We detected high T-cell infiltration and high expression of immune checkpoints and IFN-g 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 analysis in patients with relapsed/refractory AML treated with flotetuzumab, an investigational immunotherapy, showed efficacy in individuals with altered TP53 status and identified immune gene signature that support the prediction of therapeutic 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.


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