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Developing Combinational Immunotherapies Targeting Tumor Receptor Tyrosine Kinases

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Developing Combinational Immunotherapies Targeting Tumor Receptor Tyrosine Kinases DEVELOPING COMBINATIONAL IMMUNOTHERAPIES TARGETING TUMOR RECEPTOR TYROSINE KINASES by Mayumi Kawabe B.S. Applied Chemistry, Waseda University, 1988 M.S. Applied Chemistry, Waseda University, 1991 Submitted to the Graduate Faculty of School of Medicine in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2009 i UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE This dissertation was presented by Mayumi Kawabe It was defended on August 3, 2009 and approved by Robert J. Binder Ph.D, Assistant Professor, Department of Immunology Jeffrey L. Brodsky Ph.D, Professor, Department of Biological Sciences Merrill J. Egorin M.D, Department of Medicine Paul D. Robbins Ph.D, Professor, Department of Microbiology and Molecular Genetics Russell Salter Ph.D, Professor, Department of Immunology Dissertation Advisor: Walter J. Storkus Ph.D, Professor, Department of Immunology ii Copyright © by Mayumi Kawabe 2009 iii DEVELOPING COMBINATIONAL IMMUNOTHERAPIES TARGETING TUMOR RECEPTOR TYROSINE KINASES Mayumi Kawabe, PhD University of Pittsburgh, 2009 Current immunotherapies designed to stimulate specific T cell-mediated immunity have thus far yielded modest objective clinical response rates, despite the increase of tumor-specific T cells have been observed in treated patient blood. Since the majority of tumor antigens being targeted in immunotherapies are non-mutated, “self” antigens, current clinical results may relate, in part, to the low-to-moderate avidity, negatively-selected T cell repertoire in patients that is being asked to regulate tumor progression. In the current thesis, I hypothesized that by conditionally enhancing the proteasomal degradation of tumor antigens, I could generate a “synchronized” pool of derivative peptides that could then be presented in a “wave-like” temporal fashion in MHC class I complexes on the tumor cell surface. For at least a transient period thereafter, I theorized that specific CD8+ T cell recognition and anti-tumor activities would be improved. I selected a family of tumor-associated antigens, receptor tyrosine kinases (RTK) for study, as their overexpression has been linked with poor clinical prognosis in many forms of cancer. In this thesis, I show that EphA2 agonists, as well as, HSP90 inhibitors effectively promote EphA2 degradation via a proteasome- dependent manner, providing the delivery of EphA2 peptides into the classical MHC class I presentation pathway. I also show that specific CD8+ T cell recognition of EphA2 peptides derived from both the extracellular and intracellular domains of this transmembrane protein was improved as a consequence of tumor cell treatment with these agents being in consistent with the use of TAP- and ER-associated degradation. Notably, the combination of both drugs further enhanced anti-EphA2 T cell recognition of tumor cells, suggesting these modalities work via complementary, but not identical mechanisms. Importantly, complete tumor eradication was achieved in vivo (in a Hu-SCID tumor model) using a combinational therapy consisting of agonist administration just prior to the adoptive transfer of human anti-EphA2 CD8+ T cells, where either single modality was minimally beneficial. iv Preliminary data from additional studies targeting the tumor cell-overexpressed RTKs, Her2/neu and EGFR, suggest that this core treatment paradigm may be generalizeable to many (if not all) RTKs. v TABLE OF CONTENTS PREFACE..................................................................................................................................... xii 1. INTRODUCTION ...................................................................................................................... 1 1.1. Receptor Tyrosine Kineses ............................................................................................. 2 1.2. EphA2 Overview ............................................................................................................ 5 1.2.1. Eph Receptor and ephrin Ligands........................................................................... 5 1.2.2. EphA2 ..................................................................................................................... 6 1.3. Regulation of EphA2 Expression ................................................................................... 7 1.3.1. EphA2 Expression and Life Cycle in Non-transformed Tissues...................... …..7 1.3.2. EphA2 and PTPs..................................................................................................... 8 1.3.3. Genetic Regulation of EphA2............................................................................... 10 1.4. Signaling Through EphA2 ............................................................................................ 11 1.4.1. MAPK................................................................................................................... 11 1.4.2. FAK....................................................................................................................... 12 1.5. Role of EphA2 in Cancer.............................................................................................. 13 1.5.1. Overexpression of EphA2 in Cancer .................................................................... 13 1.5.2. Mechanism of EphA2 Overexpression in Cancer................................................. 14 1.5.3. Role(s) of EphA2 in Tumorigenesis ..................................................................... 15 1.5.4. Angiogenesis......................................................................................................... 16 1.6. Therapeutic Approaches Targeting EphA2 .................................................................. 18 1.6.1. Interventions Targeting EphA2 Activation/Degradation...................................... 18 1.6.1.1. Anti-EphA2 Antibodies ............................................................................... 18 1.6.1.2. Ephrin-A1 Fc................................................................................................ 19 1.6.1.3. Peptide Mimetics.......................................................................................... 20 1.6.2. Interventions Targeting EphA2 Ligands............................................................... 20 1.6.3. Gene Silencing by siRNA..................................................................................... 20 1.6.4. EphA2-based vaccines.......................................................................................... 21 1.7. Cancer Immunogy......................................................................................................... 22 1.7.1. Immunosurveillance; Immune response to cancer................................................ 22 1.7.2. Immunoevasion..................................................................................................... 24 1.7.3. Immunotherapy..................................................................................................... 26 1.8. CD8+ Cytotoxic T cell-meidated Immunity.................................................................. 28 1.8.1. Generation and Functions Mediated by CD8+ Cytotoxic T cells ........................ 29 1.8.2. MHC class I Antigen Presentaion Pathway.......................................................... 31 1.8.3. Tumor Antigens ...................................................................................................34 1.8.4. CD8+ Cytotoxic T cells Specific for Tumor Antigens ......................................... 35 vi 1.9. Approaches to Increase RTK-derived Epitope Presentation by Tumor Cell MHC class I Complexes .............................................................................................................................. 36 1.9.1. RTK Agonists and PTP Inhibition........................................................................ 37 1.9.2. HSP90 Inhibition.................................................................................................. 39 1.9.2.1. HSP90 .......................................................................................................... 39 1.9.2.2. HSP90 Inhibitors.......................................................................................... 40 Scope of This Thesis..................................................................................................................... 42 Preface Chapter 2.......................................................................................................................... 43 2.Enhancement in Specific CD8+ T Cell Recognition of EphA2+ Tumors after Treatment with Ligand Agonists............................................................................................................................ 44 2.1. ABSTRACT.................................................................................................................. 45 2.2. INTRODUCTION ........................................................................................................ 46 2.3. MATERIALS AND METHODS.................................................................................. 48 2.3.1. Cell lines and Media ............................................................................................. 48 2.3.2. Peptides................................................................................................................. 48 2.3.3. Mice .....................................................................................................................
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