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Role of Innate Immunity Activators in the Treatment of Acute Myeloid Leukemia Dissertation Presented in Partial Fulfillment Of Role of Innate Immunity Activators in the Treatment of Acute Myeloid Leukemia Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Nathaniel J. Buteyn, B.S. Graduate Program in Molecular, Cellular, and Developmental Biology The Ohio State University 2019 Dissertation Committee: Susheela Tridandapani, PhD; Advisor James Blachly, MD John Byrd, MD Amanda Toland, PhD Copyright by Nathaniel J. Buteyn 2019 Abstract Immune cells of myeloid origin have a unique role in the body’s response to non- self entities. The cells, including monocytes and macrophages, carry out a diverse array of functions including phagocytosis, the uptake and presentation of foreign antigens, environmental debris, and damaged cells; the release of cytokines that coordinate acute inflammatory responses; and cytotoxic effector functions that result in the destruction of targets. In acute myeloid leukemia (AML), a differentiation block in the myeloid cell lineage prevents proper maturation of monocytes and macrophages. Instead, leukemic blasts rapidly accumulate and proliferate in the bone marrow, blood, and organs preventing proper hemocytic development. Patient death is caused mainly by infection, followed by hemorrhage and organ failure. The most common form of adult leukemia, AML has a low five year survival rate of 26.6% and a high rate of patient relapse. Taken with the high average age of diagnosis and the fact that certain elderly patients are unable to participate in the standard treatment of high-intensity chemotherapy, it is clear that there is a need for innovative, less toxic therapeutic approaches to the disease. One such approach is the re-invigoration of the patient’s own immune system, typically suppressed in a myriad of ways due to the disease. This is explored in two novel studies presented here. The first, detailed in Chapter 2, takes advantage of the effector ii function that myeloid cells naturally possess; expression of Fcγ receptors on the cell surface allow for interaction with antibody opsonized targets. By eliciting expression of the antigen for the α-CD38 antibody daratumumab on the surface of AML blasts with all-trans retinoic acid (ATRA), we demonstrated it was possible to induce antibody- dependent blast-to-blast killing amongst the cancer itself, with blasts functioning as both targets and effectors, a phenomenon we termed fratricide. This antibody-induced fratricide showed efficacy in two mouse models of AML, decreasing tumor burden and extending survival time. The study outlined in Chapter 3 offers another approach to reactivate the innate immune system in AML. Here, the use of a synthetic bacterial peptide that induces a robust inflammatory response was examined. The peptide, muramyl tripeptide phosphatidylethanolamine (MTP-PE), together with the pro-inflammatory cytokine interferon gamma (IFN-γ), stimulates the intracellular pathogen recognition receptor NOD2, resulting in caspase-1 dependent blast apoptosis and pro-inflammatory cytokine production. Furthermore, induction of this inflammatory response in murine models of AML results in extended survival and the maturation of disease suppressed natural killer cells, an important cytotoxic leukocyte whose activation has been shown to correlate with improved outcomes in AML patients. iii The idea of harnessing the body’s natural defenses to fight malignancy has gained steam in the recent decades with the further development of innovative technologies such as CAR T cell therapy and allogeneic natural killer cell infusion. In the studies presented within, we focused not on ancillary immune cells, but rather modulating the tumor cell itself. Results gathered demonstrate potent anti-leukemic effects and suggests that these treatments may have therapeutic potential in AML. iv Vita May 2015 ................... B.S. Biotechnology, Calvin College (now Calvin University) 2015 – 2019 ................ Graduate Research Associate, MCDB program, Department of Internal Medicine, The Ohio State University Publications “Anti-leukemic effects of all-trans retinoic acid in combination with Daratumumab in acute myeloid leukemia.” NJ Buteyn, K Fatehchand, R Santhanam, H Fang, GM Dettorre, S Gautam, et al. International immunology 30 (8), 375-383 “Interferon-γ promotes antibody-mediated fratricide of Acute Myeloid Leukemia cells.” K Fatehchand, EL McMichael, BF Reader, H Fang, R Santhanam, NJ Buteyn, et al. Journal of Biological Chemistry 291 (49), 25656-25666 “CD31 acts as a checkpoint molecule and is modulated by FcγR-mediated signaling in monocytes.” G Merchand-Reyes, JP Butchar, F Robledo-Avila, NJ Buteyn, et al. Journal of Immunology November 15, 2019 Fields of Study Major Field: Molecular, Cellular, and Developmental Biology v Table of Contents Abstract ........................................................................................................................................... ii Vita .................................................................................................................................................. v List of Tables ................................................................................................................................. viii List of Figures .................................................................................................................................. ix Abbreviations ................................................................................................................................. xii CHAPTER 1: Introduction ................................................................................................................. 1 Overview of the Human Immune System .................................................................................... 1 Innate Immunity .......................................................................................................................... 2 Monocytes and Macrophages ..................................................................................................... 5 M1 vs M2 Polarization ............................................................................................................. 7 Fcγ Receptors ........................................................................................................................... 9 Acute Myeloid Leukemia .......................................................................................................... 17 Classification .......................................................................................................................... 18 Standard of Care .................................................................................................................... 22 Emerging Therapies .............................................................................................................. 24 CHAPTER 2: Anti-leukemic effects of all-trans retinoic acid in combination with daratumumab in acute myeloid leukemia ................................................................................................................ 28 Abstract ..................................................................................................................................... 28 Introduction .............................................................................................................................. 29 Acute promyelocytic leukemia ............................................................................................... 29 All-trans retinoic acid ............................................................................................................. 30 Daratumumab ........................................................................................................................ 33 Materials and Methods ............................................................................................................. 35 Results ....................................................................................................................................... 40 ATRA upregulates CD38 in AML cells ..................................................................................... 40 vi ATRA triggers daratumumab-mediated immune conjugate formation and killing in vitro... 46 Single-dose ATRA elicits CD38 upregulation and confers daratumumab activity ................. 51 ATRA synergizes with daratumumab to impede AML tumor growth and extend survival in vivo ........................................................................................................................................ 53 Discussion ................................................................................................................................. 57 CHAPTER 3: Activation of the intracellular pattern-recognition receptor, NOD2, promotes NK cell maturation and extends survival in acute myeloid leukemia ....................................................... 63 Abstract ..................................................................................................................................... 63 Introduction .............................................................................................................................. 65 Coley’s toxin ........................................................................................................................... 65 Pattern recognition receptors ...............................................................................................
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