The fundamental interest of the Myeloid Malignancies Section is the detection, prevention and treatment of AML relapse with the long-term objective of using immunotherapy without the need for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our research has involved the following four complementary approaches: Sub-project 1: Identification of unique AML leukemia associated antigens: The ability to target myeloid malignancies using immunotherapy, without allo-HSCT, depends on the capability to target leukemic clones while sparing normal tissues. A variety of putative leukemia associated antigens (LAA) for acute myeloid leukemia (AML) have been identified and consensus panels have attempted to prioritize generic cancer antigens. In an attempt to create an evidence-based list of AML antigen targets we analyzed, using a custom quantitative real-time PCR (RQ-PCR) array, gene expression of 65 potential LAAs in de-identified, highly clinically annotated samples from 48 newly diagnosed untreated adult AML patients collected under IRB-approved protocols by our collaborators at three NCCN cancer centers (Johns Hopkins, Vanderbilt and Massachusetts General) and compared with healthy normal donor peripheral blood, bone marrow and organ specific RNA profiles. This work showed that of those candidate LAAs proposed to date - a) no single LAA is expressed in every case of AML, b) all cases of AML had at least one LAA gene overexpressed compared to the upper limit seen in normal control donors c) many of the proposed LAAs were expressed in cell lines but not overexpressed in primary AML patient peripheral blood or bone marrow when compared to normal controls d) many of the LAAs were expressed in an organ specific pattern in healthy normal controls, e) overexpression of LAA was observed across multiple samples from the same patient including unsorted peripheral blood samples, sorted AML blasts and a sorted stem cell enriched (that is lineage negative, CD34 positive and CD38 negative) peripheral blood sample. Status: Project completed. Published in Leukemia, May 2014 (PMID: 24472813, PMC4013200). Sub-project 2: High sensitivity measurement of AML disease burden for patients in remission to stratify based on risk of clinical relapse and to determine efficacy of additional treatment: The ability to risk stratify patients in clinical remission into high and low risks of relapse based on persistence of molecularly detectable minimal residual disease (MRD) and quantify the efficacy of any treatment intervention by determination of changes in this MRD would be of significant utility, especially in trials of novel experimental agents such as immunotherapy. Using information derived from our study of AML antigens (above) we have developed a novel molecular panel based on a multiple gene RQ-PCR array (MG-MRD) for the high sensitivity detection of AML, which we retrospectively tested on 74 patients who underwent allo-HSCT at the NHLBI in the period 1994-2012. MG-MRD testing on peripheral blood samples prior to transplantation demonstrated excellent concordance with traditional bone marrow based evaluation and improved risk stratification for post transplant relapse and overall survival outcomes. Status: Invited presentation in educational session of International 2014 ASBMT/CIBMTR BMT Tandem Meeting. Invited reviews (PMID: 24291784) and editorials (PMID: 25016196) completed. Manuscript describing laboratory results of our multigene MRD assay in samples from AML patients undergoing allo-HSCT at NHLBI submitted. Sub-project 3: Functional characterization of the human immune system in AML patients in remission after treatment: In collaboration with the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and the trans-NIH Center for Human Immunology, Autoimmunity and Inflammation (CHI) we initiated in fall 2012 a clinical protocol (J1293) to study the functional immune capacity of AML patients after completion of chemotherapy but at continued risk of relapse. While a variety of active immunization approaches of cancer-vaccination have been previously tested in clinical trials in this population in an attempt to prevent relapse, our study represents the first attempt at a systematic deep characterization of the functional capacity of the immune systems of these patients. We used the seasonal influenza vaccine as a robust and well defined immunological challenge and combined information from 15-color flow cytometry panels, gene expression profiles, cytokine luminex, T and B cell elispot and antibody titers with clinical data including time since chemotherapy, complete blood counts and (if applicable) date of influenza infection or eventual AML relapse. Status: Patient enrollment completed. Laboratory analysis complete. Patient follow-up for clinical outcomes will continue until Spring 2015. Sub-project 4: Characterization of the disease biology characteristics and immune parameters associated with successful response to immunotherapy: Cancer immunotherapy is associated, at best, with an overall response rate rarely exceeding 50% with a complete response rate in the range 10-20%. Predictive biomarkers of response would be of great interest to the field, both practically for clinical use but also as a route to understanding the fundamental immunobiological mechanisms associated with response. We have therefore begun to study immune parameters and disease characteristics from a variety of patients treated with immunotherapy for myeloid malignancies (CML, MDS, AML) both retrospectively from completed studies but also prospectively in future studies in an attempt to elucidate disease and agent specific characteristics but also those features shared across responders. Such analysis may also serve as a benchmark for future trials. Status: Dr Hourigan has served as the principal investigator on two clinical protocols during the duration of this report, the vaccination protocol J1293 described in sub-project 3 above, and also 05-H-0206 (NIH trial of alemtuzumab in myelodysplastic syndromes) which was presented at 2013 American Society of Hematology (ASH) Annual Meeting (awarded ASH Abstract Achievement Award). Collaborations and material transfer agreements have been established with clinical investigators at Johns Hopkins and Duke University Hospitals to conduct laboratory correlates on their ongoing clinical trials of immunotherapy interventions in patients with AML. In summary, the primary interest of the Myeloid Malignancies Section is the detection, prevention and treatment of AML relapse. We intend to accomplish this by developing high sensitivity measurements of residual disease burden alongside research aimed at understanding and using immunotherapy outside of the setting of stem cell transplantation. At present this involves a coordinated, overlapping and iterative program of translational research on carefully annotated patient samples from informative clinical time-points in an attempt to quantity subclinical residual disease burden and understand the fundamental human immunobiology associated with successful responses to cancer immunotherapy in patients with myeloid malignancies.

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2
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2014
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U.S. National Heart Lung and Blood Inst
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Sheela, Sheenu; Ito, Sawa; Strich, Jeffrey R et al. (2017) Successful salvage chemotherapy and allogeneic transplantation of an acute myeloid leukemia patient with disseminated Fusarium solani infection. Leuk Res Rep 8:4-6
Lindblad, Katherine E; Goswami, Meghali; Hourigan, Christopher S et al. (2017) Immunological effects of hypomethylating agents. Expert Rev Hematol 10:745-752
Goswami, Meghali; Prince, Gabrielle; Biancotto, Angelique et al. (2017) Impaired B cell immunity in acute myeloid leukemia patients after chemotherapy. J Transl Med 15:155
Hourigan, Christopher S (2017) Editorial: Targets for Immunotherapy in Acute Leukemia. Curr Drug Targets 18:256
Cheng, M Jennifer; Smith, B Douglas; Hourigan, Christopher S et al. (2017) A Single Center Survey of Health-Related Quality of Life among Acute Myeloid Leukemia Survivors in First Complete Remission. J Palliat Med :
Buckley, Sarah A; Wood, Brent L; Othus, Megan et al. (2017) Minimal residual disease prior to allogeneic hematopoietic cell transplantation in acute myeloid leukemia: a meta-analysis. Haematologica 102:865-873
Percival, Mary-Elizabeth; Lai, Catherine; Estey, Elihu et al. (2017) Bone marrow evaluation for diagnosis and monitoring of acute myeloid leukemia. Blood Rev 31:185-192
Hourigan, C S; Gale, R P; Gormley, N J et al. (2017) Measurable residual disease testing in acute myeloid leukaemia. Leukemia 31:1482-1490
Lai, Catherine; Karp, Judith E; Hourigan, Christopher S (2016) Precision medicine for acute myeloid leukemia. Expert Rev Hematol 9:1-3
Hourigan, Christopher S; Aplan, Peter D (2016) Accurate Medicine: Indirect Targeting of NPM1-Mutated AML. Cancer Discov 6:1087-1089

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