Understanding mechanisms of impaired immunity in the AML bone marrow

PROJECT SUMMARY/ABSTRACT Immune-based treatments for acute myeloid leukemia (AML), an aggressive hematologic malignancy that remains fatal for over half of the 20,000 patients diagnosed in the United States annually, remain an unmet clinical need. The impetus to use T cell-based immunotherapy approaches for AML treatment is underscored by the curative potential of allogeneic hematopoietic cell transplantation for AML, arising from immune- mediated graft-versus-leukemia activity of donor T cells, and by emerging correlative data between the immune landscape and AML treatment efficacy. Understanding mechanisms of ineffective anti-leukemic T cell activity in the AML bone marrow (BM), the site where AML emerges, is fundamental for advancing immunotherapeutic approaches for AML. Our preliminary data highlight the immunosuppressive nature of T cells within the AML BM, the dynamic evolution of T cell clones with regard to states of T cell activation and exhaustion, and the immunomodulatory potential of malignant AML cells on T cells. We hypothesize that both malignant and non-malignant cells in the AML BM promote impaired T cell immunity, leading to distinct T cell compositions at different disease states. This career development program will address two specific aims: (1) determine T cell intrinsic features that affect the relationship between T cell phenotype, repertoire, and disease status in the AML BM, and (2) understand mechanistically how malignant (AML blasts) and non-malignant cells in the AML BM shape features of the T cell compartment. The candidate has developed this proposal as an extension of her ongoing T cell studies in hematologic malignancies and clinical experience in AML. During the award period, she will complete her research with close counsel from her primary mentor, Omar Abdel-Wahab, MD, an accomplished scientist in leukemia biology and genomics who is the Chair of the MSK Molecular Pharmacology Program. Additional input will be offered by her co-mentor, Marcel van den Brink, MD, PhD, an international expert in T cell biology in hematologic malignancies, and by her Advisory Committee. Drs. Abdel-Wahab and van den Brink are both mentors with outstanding records of navigating physician–scientists toward research independence. Under their guidance, the candidate will develop skills that are critical for her future laboratory program, including learning to generate and analyze syngeneic mouse models of AML, to build upon her knowledge of functional studies with primary AML samples, and to advance her computational and bioinformatics abilities in sequencing-based immunologic techniques. Completion of this proposal will provide the candidate with the training and mentorship required to cultivate and refine her expertise in T cell immunology and leukemia research and to establish her academic career as an independent laboratory-based clinical investigator dedicated to advancing immunologic treatments for AML.