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An Overview of Acute Myeloid Leukemia and Cancer Immunology: (I) Concepts and Therapeutic Strategies and (Ii) Repsox As a Candidate Cell-Engineering Tool

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Graduate Theses, Dissertations, and Problem Reports 2014 An Overview of Acute Myeloid Leukemia and Cancer Immunology: (i) Concepts and Therapeutic Strategies and (ii) RepSox as a Candidate Cell-Engineering Tool Audrey Nadine Jajosky Follow this and additional works at: https://researchrepository.wvu.edu/etd Recommended Citation Jajosky, Audrey Nadine, "An Overview of Acute Myeloid Leukemia and Cancer Immunology: (i) Concepts and Therapeutic Strategies and (ii) RepSox as a Candidate Cell-Engineering Tool" (2014). Graduate Theses, Dissertations, and Problem Reports. 5874. https://researchrepository.wvu.edu/etd/5874 This Dissertation is protected by copyright and/or related rights. It has been brought to you by the The Research Repository @ WVU with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you must obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in WVU Graduate Theses, Dissertations, and Problem Reports collection by an authorized administrator of The Research Repository @ WVU. For more information, please contact [email protected]. An Overview of Acute Myeloid Leukemia and Cancer Immunology: (i) Concepts and Therapeutic Strategies and (ii) RepSox as a Candidate Cell-Engineering Tool Audrey Nadine Jajosky Dissertation submitted to the West Virginia University School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Cancer Cell Biology Michael Ruppert, MD, PhD, Chair Linda Vona-Davis, PhD Steven Frisch, PhD Karen Martin, PhD William Tse, MD Laura F. Gibson, PhD, mentor Cancer Cell Biology Program Morgantown, West Virginia 2014 Key words: RepSox (E 616452), acute myeloid leukemia (AML), CD34+ AML cells, Tim-3, CXCL12 (SDF-1), cancer immunotherapy, TGF-β, c-Myc, CXCR4, CXCR7, γ9δ2 T cells, reprogramming, cell engineering, co-culture, cancer stem cells, immunogenicity, immunologic synapse, aldehyde dehydrogenase (ALDH), ALK5 ABSTRACT An Overview of Acute Myeloid Leukemia and Cancer Immunology: (i) Concepts and Therapeutic Strategies and (ii) RepSox as a Candidate Cell-Engineering Tool Audrey Nadine Jajosky This dissertation is intentionally broad in scope and describes the conceptual frameworks, research advances, and clinical successes that inspired a therapeutic vision that, in turn, prompted specific RepSox experiments (Jajosky, 2014). The goal of this dissertation is to guide and encourage students interested in engineering anti-cancer immune therapies by providing perspective and suggestions. Chapter I provides background on acute myeloid leukemia (AML), the cancer stem cell (CSC) theory, and the chemical reprogramming tool “RepSox.” Chapter II describes how tumor cells passively evade immune recognition and actively suppress immune cells to escape destruction. Immunotherapeutic strategies are described that increase tumor-cell immunogenicity and/or sensitize tumor cells to immune-mediated death. Chapter III reviews immune-cell defects induced by cancer-distorted microenvironments. Tumor cells alter local physical and metabolic conditions and distort surrounding stromal cells in ways that impair infiltrating immune cells and promote cancer progression. Strategies are described that can reverse immune-cell defects and improve anti-tumor immunity. Chapter IV highlights successful cancer immunotherapies, including patient-specific, FDA-approved, and AML leukemic stem cell (LSC)-targeted strategies. These therapies involve antibodies, activated immune cells, and/or immuno-modulatory agents designed to eradicate tumor cells, repair and activate dysfunctional immune cells, and reduce cancer-induced immune suppression in tumor microenvironments. Chapter V describes the features and rationale of a therapeutic vision that, in combination with recent clinical and research findings, guided this project and identified specific technical obstacles. Chapter VI is the published study – entitled “RepSox slows decay of CD34+ acute myeloid leukemia cells and decreases T cell immunoglobulin mucin-3 expression” – which describes how RepSox, a “small molecule” reprogramming tool and TGF-β inhibitor, affects AML cells. The key findings are RepSox (1) slows decay of primary CD34+ AML cells from patients with diverse AML disease, (2) increases CXCL12 and MYC, and (3) accelerates loss of Tim-3, an inhibitory (immune-checkpoint) receptor, from the surface of AML cells. Thus, RepSox may promote in vitro engineering of patient-specific AML LSC-targeted therapies by prolonging survival of primitive CD34+ AML cells and increasing AML-cell immunogenicity via Tim-3 reduction. When envisioning the immunologic synapse between antigen- presenting AML cells and T cells, the actions of RepSox suggest RepSox might promote in vitro T-cell activation against primitive (relapse-causing) AML cells which represent the most problematic therapeutic target. Chapter VII discusses the potential therapeutic applications of these results in the context of AML and other cancers as well as unanswered questions and future research options. For example, the actions of RepSox suggest that its incorporation into pre-existing co-culture methods that exploit TCR agonists may enhance the activation of γδ T cells against a patient’s primitive AML cells and, thereby, help generate more effective immune-cell therapies. One goal of this dissertation is to encourage students to integrate new findings and conceptual frameworks from immunology, regenerative medicine, and cancer research when deciding which exciting research agendas to pursue. DEDICATION This project was sustained by reviewing, as needed, fascinating stories about past cancer fighters – like those remarkable volunteers in the "Women's Field Army" (1936) immortalized by their "sword of hope" – and by receiving support from the optimistic and creative students and faculty at West Virginia University. In my future endeavors as a physician-scientist, I hope to honor the memory of NCI’s Dr. Alessandra Margherita Bini whose death – by cancer – prevented me from thanking her for four years of NIH support. i ACKNOWLEDGMENTS Patients treated at WVU’s Mary Babb Randolph Cancer Center donated their leukemia specimens so this research could be conducted. To them I am indebted, and I intend to “pay their altruism forward.” My mentor, Dr. Laura Gibson, members of my PhD committee, Dr. Linda Vona-Davis, Dr. Steven Frisch, Dr. Karen Martin, Dr. Michael Ruppert, Dr. William Tse, and Dr. Fred Minnear were helpful in ways that went beyond insightful suggestions and guidance. Most notably, they fostered a creative environment that inspired me to “have no fear,” design my own project, and have it critiqued by experts at the National Cancer Institute (NCI). For four years, a sense of gratitude for the NCI grant award motivated me – especially when working in the lab at 3-am. Cancer researchers at NCI felt I had potential, and I am grateful. At WVU, the examples set by clinicians and scientists showed me how to collaborate and have fun while learning from others. Staff in the Gibson lab, WVU's Pathology Department, and flow cytometry and imaging facilities provided not just technical help but laughs and wonderful memories that make me smile. WVU's “Osborn Program” retreats reminded me that patients are the reason we work as hard as we do and that human suffering engenders a sense of urgency that can drive the creativity that helps us solve technical problems. Daniel Vanderbilt, my MD-PhD classmate, has been a wonderful friend. His constant support, commitment to science, and words of encouragement have inspired and comforted me. Overall, I am impressed by how the MD-PhD community at WVU has succeeded in creating a nurturing and creative intellectual environment. I am grateful to the patients, scientists, physicians, staff, students – and supportive neighbors – for all the fun and laughs in Morgantown, a truly exciting “college town.” Go Mountaineers! ii TABLE OF CONTENTS Dedication ........................................................................................................................ i Acknowledgements .......................................................................................................... ii Table of contents ............................................................................................................. iii List of abbreviations ....................................................................................................... vii List of tables .................................................................................................................... x List of figures ................................................................................................................... xi Preface .................................................................................................................................... 1 Chapter I: Background on Acute Myeloid Leukemia, the Cancer Stem Cell Theory, and the TGF-β inhibitor “RepSox” ...................................................................................... 3 Pathogenesis ........................................................................................................ 4 Subtypes .............................................................................................................
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