Resistance to Immunotoxins in Cancer Therapy (Resistance to Targeted Anti-Cancer Therapeutics Book 6)

This book will be a guide to understanding resistance against targeted therapeutic approaches for cancer using immunotoxins. It contains a detailed review of the history and development of targeted therapy. As well, it includes an in-depth description of the molecular and cellular mechanisms involved in cancer resistance and several novel methods to overcome resistance. Each chapter discusses different aspects of resistance and covers all the factors that may contribute to resistance in cancer cells. Finally, this volume highlights the recent findings and advances associated with tackling cancer resistance. Preface 6 About the Editor 8 Contents 9 Contributors 15 Chapter-1 17 Targeted Cancer Therapy: History and Development of Immunotoxins 17 1.1 Introduction 19 1.2 Chemotherapy 19 1.3 Cancer Immunotherapy 20 1.3.1 Antibodies in Cancer Therapy 20 1.3.2 Tumor Antigens 21 1.3.3 Antibodies for the Clinic 21 1.3.4 Antibodies as Carriers 22 1.4 Immunotoxins in Cancer Therapy 24 1.4.1 Targeting Moiety 25 1.4.2 Toxins in Cancer Immunotherapy 26 1.5 Construction of an Immunotoxin 33 1.6 Internalization and Cytotoxic Activity of Immunotoxins 33 1.7 Immunotoxins in Clinical Study 34 1.8 Conclusions 41 References 42 Chapter-2 48 Immunotoxins, Resistance and Cancer Stem Cells: Future Perspective 48 2.1 Introduction 49 2.2 Factors Responsible for Cancer Resistance 50 2.2.1 Gene Mutations in Signalling Pathways 50 2.2.2 Drug Transporters 51 2.2.3 Tumor Microenvironment and Accessibility 51 2.3 Resistance to Immunotoxins 52 2.3.1 Dysfunctional Apoptotic Pathways 52 2.3.2 ABC Transporters 55 2.3.3 Lysosomal Degradation 55 2.3.4 Other Factors 56 2.4 Cancer Stem Cells and Resistance 56 2.4.1 Drug Efflux 56 2.4.2 Detoxification and Cellular Repair 57 2.4.3 DNA Repair and Modification 58 2.4.4 Survival Pathways 59 2.4.5 Autophagy and EMT 59 2.4.6 Quiescence 59 2.4.7 Microenvironment 59 2.5 Strategies Used to Overcome Resistance 60 2.5.1 Inhibitors of Anti-apoptotic Proteins 60 2.5.2 Blocking Membrane Drug Transporters 61 2.5.3 Delivery and Intracellular Trafficking 61 2.5.4 Inhibition of DNA Repair and Telomerase Activity 61 2.5.5 Combination Therapy 62 2.5.6 Nanotechnology 63 2.5.7 Other Novel Strategies 63 2.6 Targeting Cancer Stem Cells 64 2.6.1 Targeting Signaling Pathways in CSC’s 64 2.6.2 Targeting Apoptosis and Cellular Repair Mechanisms in CSC’s 65 2.6.3 Targeting Autophagy and Microenvironment in CSC’s 66 2.6.4 Targeting Membrane Transporters and CSC Surface Markers 66 2.7 Conclusion 66 References 67 Chapter-3 72 Factors that Determine Sensitivity and Resistances of Tumor Cells Towards Antibody-Targeted Protein Toxins 72 3.1 Introduction 73 3.2 Intoxication Pathways Define Determinants for Sensitivity and/or Resistances of Tumor Cells Towards Immunotoxins 75 3.3 Step 1—Access to Target Cells: Immunogenicity can be a Relevant Factor for Immunotoxin Therapy 77 3.4 Step 2—Target Cell Binding: Loss or Reduction of Target Antigens Reduce Sensitivity of Tumor Cells Towards Targeted Toxins 78 3.5 Step 3—Entry of Toxins into Cells: Loss of Processing Enzymes and Modulation of Vesicular Compartments Reduce Toxin Activity in Cultured Cells 79 3.6 Step 4—ADP-Ribosylation of eEF2: Reduced or Altered Expression of Diphthamide Synthesis Genes is Associated with Immunotoxin Resistances 80 3.7 Step 5—Signaling and Apoptosis: Protective Factors and Pathways can Reduce Toxin Sensitivity 81 3.8 Conclusions and Outlook 83 References 84 Chapter-4 89 Cell Signaling and Resistance to Immunotoxins 89 4.1 Introduction 90 4.2 Conceptual Considerations on Cellular Immunotoxin Resistance 91 4.2.1 Alteration of Immunotoxin Resistance via Modulation of Caspase Activation Pathways 92 4.2.2 Resistance Mediated by the Cellular Apoptosis Susceptibility Gene 94 4.2.3 Resistance Mediated by Insulin-Like Growth Factor Signaling 94 4.2.4 Immunotoxin Resistance via Interference with Diphthamide Synthesis 94 4.2.5 Modulation of Immunotoxin Resistance via PI3K/AKT Signaling 95 4.2.6 Immunotoxin Resistance via Drug Transporter Activity 95 4.2.7 Modulation of Immunotoxin Resistance via Cytokine Signaling 96 4.2.8 Modulation of Immunotoxin Resistance via Protein Kinase C Signaling? 96 4.3 Conclusion 97 References 97 Chapter-5 102 Antibody-Drug Conjugates and Immunotoxins for the Treatment of Hematologic Neoplasms 102 5.1 Introduction 104 5.2 Anti-CD33 Immunotoxins for Acute Myeloid Leukemia 104 5.2.1 Gemtuzumab Ozogamicin 107 5.2.2 AVE9633 110 5.2.3 HUM-195/rGEL 111 5.2.4 SGN-CD33A 111 5.3 Antibody-Drug Conjugates for B-Cell Lymphoid Malignancies 112 5.3.1 Anti-CD22 Immunotoxins 112 5.3.1.1 Inotuzumab Zogamycin 112 5.3.1.2 BL22 115 5.3.1.3 Moxetumomab Pasudotox 116 5.3.1.4 Pinatuzumab Vedotin 116 5.3.2 Anti-CD25 Immunotoxins 117 5.3.3 Anti-CD19 Immunotoxins 117 5.3.3.1 SAR-3419 117 5.3.3.2 Combotox 118 5.3.3.3 DT2219ARL 121 5.3.3.4 SGN-CD19A 121 5.3.4 Anti- CD70 Immunotoxins 122 5.3.4.1 MDX-1203 122 5.3.4.2 SGN-75 122 5.3.5 Anti-CD79: Polatuzumab Vedotin 123 5.3.6 Anti-CD30: Brentuximab Vedotin 123 5.3.7 Anti-CD37: IMGN529 124 5.4 Immunotoxins for T-Cell Lymphoid Malignancies 125 5.4.1 Brentuximab Vedotin 125 5.4.2 Denileukin Diftitox 127 5.4.3 A-dmDT390-bisFv (UCHT1) 128 5.5 Hodgkin Lymphoma 129 5.6 Immunoconjugates for Multiple Myeloma 130 5.6.1 Milatuzumab-Doxorubicin Antibody-Drug Conjugate 130 5.6.2 Indatuximab Ravtansine 131 5.6.3 Lorvotuzumab Mertansine 132 5.7 Conclusions 133 References 134 Chapter-6 142 Challenges for Therapeutic Application of Pseudomonas Exotoxin-Based Immunotoxins 142 6.1 Introduction 143 6.2 Immunotoxins 144 6.3 Brief Historical Overview of PE-Based ITs 145 6.4 Immunogenicity of PE-based RITs and Solutions for Reducing it 150 6.5 Limited Stability of PE-Based RITs and How it Was Overcome by Antibody and Toxin Engineering 158 6.6 Insufficient Potency and Combining Therapies to Enhance Potency 161 6.7 Potentiation of RITs by Affinity Maturation of the Targeting Antibody 165 6.8 Reducing Off-Target Toxicity and Overcoming Physical Barriers 167 References 170 Chapter-7 178 Drug Resistance to Calicheamicin Conjugated Monoclonal Antibody Therapy 178 7.1 Introduction 179 7.2 CD33 180 7.2.1 Gentuzumab Ozogamicin (GO) 181 7.2.2 GO Monotherapy, Phase I Study 182 7.2.3 Phase II Study 183 7.2.4 Drug Resistance via P-glycoprotein 183 7.2.5 GO Treatment with MDR Modifier, CyA 184 7.2.6 Drug Resistance Other Than P-glycoprotein 185 7.2.7 Phase III Study with GO for AML and Disappearance from the Market 186 7.2.8 Subsequent Phase III Study for AML 187 7.2.9 The Efficacy of GO for Acute Promyelocytic Leukemia (APL) 188 7.3 CD22 189 7.3.1 Inotuzuma Bozogamicin 189 7.3.2 Drug Resistance of IO 189 7.4 Conclusion 190 References 190 Chapter-8 197 Engineered Versions of Granzyme B and Angiogenin Overcome Intrinsic Resistance to Apoptosis Mediated by Human Cytolytic Fusion Proteins 197 8.1 Introduction: From Classical Immunotoxins to Human Cytolytic Fusion Proteins 199 8.2 Human Granzyme B 202 8.2.1 The Role of Granzyme B in Immune Surveillance 202 8.2.2 Therapeutic Potential and Limitations of Granzyme B for the Treatment of Cancer 205 8.2.3 Regulation of Granzyme B Activity by PI-9 206 8.2.4 Therapeutic Options to Restore the Sensitivity of PI-9-Positive Tumors Against Granzyme B 208 8.2.4.1 Downregulation of PI-9 Expression and Activity 208 8.2.4.2 Design of Granzyme B Variants that are Insensitive Towards PI-9 209 8.2.4.3 Therapeutic Efficacy of hCFPs Based on GrBR201K 210 8.3 Human Angiogenin 211 8.3.1 Targeted Cell Depletion Using Human Angiogenin 213 8.3.2 Generation of Angiogenin Mutants with Improved Cytotoxicity 215 8.3.2.1 Enhancing Cytosolic Translocation and Retention 215 8.3.2.2 Increasing the Enzymatic Activity of Angiogenin 216 8.3.2.3 Reducing the Susceptibility of Angiogenin to Inhibition 216 8.3.2.4 Angiogenin Variants with Several Modified Properties 217 8.4 Conclusion 218 References 218 Chapter-9 232 Therapeutic Impact of Immune Responses in Cancer 232 9.1 Introduction: Milestones in Cancer Research 233 9.2 Immunotherapies at the Beginning of the Twenty-First Century 236 9.3 Cell-Based Cancer Immunotherapies 237 9.4 Tumor Cells Transgenic for Cytokines Used in ACT 239 9.5 Antigen Presenting Cells Transgenic for Tumor Antigens Used in Adoptive Cell Transfer 246 9.6 T Cells Used in Adoptive Cell Transfer 248 References 250 Index 257 Front Matter....Pages i-xvi Targeted Cancer Therapy: History and Development of Immunotoxins....Pages 1-31 Immunotoxins, Resistance and Cancer Stem Cells: Future Perspective....Pages 33-56 Factors that Determine Sensitivity and Resistances of Tumor Cells Towards Antibody-Targeted Protein Toxins....Pages 57-73 Cell Signaling and Resistance to Immunotoxins....Pages 75-87 Antibody-Drug Conjugates and Immunotoxins for the Treatment of Hematologic Neoplasms....Pages 89-128 Challenges for Therapeutic Application of Pseudomonas Exotoxin-Based Immunotoxins....Pages 129-164 Drug Resistance to Calicheamicin Conjugated Monoclonal Antibody Therapy....Pages 165-183 Engineered Versions of Granzyme B and Angiogenin Overcome Intrinsic Resistance to Apoptosis Mediated by Human Cytolytic Fusion Proteins....Pages 185-219 Therapeutic Impact of Immune Responses in Cancer....Pages 221-245 Back Matter....Pages 247-249 This volume is a guide to understanding resistance against targeted therapeutic approaches for cancer using immunotoxins. It contains a detailed review of the history and development of targeted therapy. As well, it includes an in-depth description of the molecular and cellular mechanisms involved in cancer resistance and several novel methods to overcome resistance. Each chapter discusses different aspects of resistance and covers all the factors that may contribute to resistance in cancer cells. Finally, this volume highlights the recent findings and advances associated with tackling cancer resistance