Experimental and Applied Immunotherapy (eBook)

Experimental and AppliedImmunotherapy 3
Copyright 4
Foreword (Précis) 5
Contents 9
Contributors 13
Part I T Cell Therapy: State-of-the-Art 19
Chapter 1: Extending the Use of Adoptive T Cell Immunotherapy for Infections and Cancer 20
Current State of Translational T Cell Therapy 21
Immunotherapy for Viral Infections Post-HSCT 21
Cytomegalovirus (CMV) 21
Epstein-Barr Virus (EBV) 21
Other Viruses 22
Immunotherapy for Virus-Associated Malignancies 22
EBV Lymphoma 22
Immunotherapy for Melanoma 25
T Cells Directed Against Nonviral Antigens 27
Classification of Tumor Antigens 28
Tumor Antigens and T-Cell Immunogenicity 28
Identification of Novel Tumor Antigens 28
Optimizing Cell Culture Protocols for Tumor-Specific CTL Generation 29
Antigen-Presenting Cells (APCs) 29
Cytokines 30
Genetic Modification of T Cells 31
Redirecting T-cell Specificity (Genetic Modification) 31
TCR Gene Transfer 31
Genetic Modification with Chimeric Antigen Receptors 34
Clinical Studies 34
Genetic Modification of T Cells to Improve in vivo Proliferation and Survival 35
T-cell Persistence and Survival in vivo 35
T-cell Sources for Genetic Modification 36
Gene Modification to Enhance T-Cell Proliferation 36
Manipulating the Infused T Cells to Counteract Tumor Evasion Strategies 37
Genetic Modification of T Cells to Improve Safety 38
Suicide Genes 38
Targeted Integration 39
Counteracting the Tumor Microenvironment 40
Nonspecific Lymphodepletion 40
Specific Treg Depletion 40
Scale-Up of Tumor CTL Therapy 41
Simplify Large-Scale CTL Production 41
“Off the Shelf.” CTLs Cells 42
Cost Effectiveness of Adoptive T-Cell Therapy versus Conventional Therapies 43
References 44
Part II Non-T Cell Therapeutic Approaches 51
Chapter 2: B Lymphocytes in Cancer Immunology 52
Introduction 53
Peripheral Human B-cell Development 53
B-Cell Effector States 55
B Cells and Cancer 57
Serology 57
Tumor-Infiltrating B Cells 58
B Cells and Cancer: Friends or Foes? 58
Evidence for a Protective Effect of B Cells in Antitumor Responses 59
Evidence for a Negative Effect of B Cells on Antitumor Responses 60
Chronic Lymphocytic Leukemia as a Paradigm for Tumor Promotion by B Cells 62
B-Cell-Directed Cancer Immunotherapy 64
Eliminating Negative B-Cell Effects 64
Promoting Positive B-Cell Effects 65
Vaccines and Recombinant Antibodies 65
Enhancing B-cell Activity In situ 66
Adoptive B-Cell Transfer 66
References 67
Chapter 3: Monoclonal Antibody Therapy for Cancer 73
General Considerations 73
Introduction 73
Precision and Predictability 75
From Hematologic to Solid Malignancies 76
Direct and Indirect Mechanisms of Activity 80
Antigen 81
Antibody Engineering 82
Structural Features 82
Chimeric, Humanized, and Fully Human mAbs 83
Fc Engineering 85
Beyond IgG 85
Clinical Performance 86
Overview 86
CD20 Targeting 87
ERBB Receptor Family Targeting 88
VEGFA Targeting 90
Outlook 91
References 92
Chapter 4: Natural Killer Cells for Cancer Immunotherapy 98
NK Cell Development and Identification 98
Effector Functions of NK Cells 100
NK-Target Cell Recognition and Regulation by Cell Surface Receptors 101
Inhibitory Receptors 103
KIRs 103
NKG2A/CD94 Heterodimer 104
Activating Receptors 104
NKG2D 104
Natural Cytotoxicity Receptors (NCR) 105
CD16 (Fcg.RIII) 105
DNAM-1 (CD226) 105
Extrinsic Regulation of NK Cells 106
Role of NK Cells in Cancer 106
Clinical use of NK Cells 107
Adoptive Immunotherapy 107
Strategies that Target NK Cells 110
Antibody Therapies 110
Engaging Activating Signals 111
Blocking Inhibitory Signals 112
Chemotherapeutic Drugs 112
Conclusions and Future Challenges 112
References 113
Chapter 5: Dendritic Cell-Based Cancer Vaccines: Practical Considerations 119
Introduction 119
Dendritic Cell Biology 120
Autologous Clinical Vaccine Trials 122
Clinical Dendritic Cell Studies: Issues Facing the Field 122
DC Source and Vaccine Manufacture 122
Antigen Loading of DCs 126
Route of Administration 128
Cancer Type: Susceptibility to DC Therapy 129
Summary 130
Issues in Clinical Trial Methodology 130
Standardization of DC Preparation 131
Immunological Parameters 131
Combination Therapy 132
Future Directions 132
References 133
Chapter 6: Mesenchymal Stromal Cells: An Emerging Cell-Based Pharmaceutical 139
Introduction and Classification 140
Physiological Functions of MSC 141
MSC and Hematopoiesis 141
PBSC Transplantation 141
MSC Homing 142
Osteogenesis Imperfecta 142
Myocardial Infarction 143
MSC Immuno-regulatory Functions 144
Background MSC Immune Characteristics 144
MSC and Immunosuppression: Direct versus Indirect T-Cell Inhibition 144
Direct T-Cell Immunosuppression 145
Indirect T-Cell Immunosuppression 145
Via Macrophages 145
Via DC 147
B Cells 147
Immunosuppressive Properties of MSC for Immunotherapy 148
MSC for the Prevention and Treatment of Steroid Refractory Acute GVHD 148
MSC for the Treatment of Arthritic Diseases 151
MSC for the Treatment of Multiple Sclerosis 151
MSC and Organ Transplantation 152
Immune Activation by MSC 152
Immune Recognition 152
MSC are Conditional APC 152
Future Objectives Regarding MSC and Immunotherapy 153
MSC and Cancer 154
Concluding Remarks 155
References 155
Part III T Cell Therapeutic Approaches 161
Chapter 7: Tumor-Specific Mutations as Targets for Cancer Immunotherapy 162
A Brief Overview of Cancer Genomics 163
Basics of Cellular Immunology and the Potential for Immune Recognition of Tumor-Specific Mutations 165
Evidence of Naturally Occurring Cellular Immunity Against Tumor-Specific Mutations 168
Clinical Immunotherapy Trials That Have Targeted Tumor-Specific Mutations 169
Ras 169
BCR-ABL 174
Roadmap for the Field 176
Summary 178
References 178
Chapter 8: Counteracting Subversion of MHC Class II Antigen Presentation by Tumors 184
Tumors and the Immune System 184
Role of Adaptive CD4+ T-Cell Responses in Tumor Eradication 186
Tumor Cells as APCs 187
Why Does the Antitumor T-Cell Response Often Prove Defective? 188
Subversion of MHC II Antigen Presentation in Tumors 188
Overview of the MHC-II Antigen Presentation Pathway 188
Patterns of MHC Class II Expression in Tumor Cells 190
Patterns of Ii Expression in Tumor Cells 192
Patterns of HLA-DM and -DO Expression in Tumors 192
Modulation of MHC II Accessory Molecules in Tumors 193
Counteracting Subversion of Antigen Presentation 194
Discovery of Novel TAAs and T-Cell Epitopes 195
Cellular Vaccines 195
Tumor Vaccines 195
DC Vaccines 196
B-Cell Vaccines 198
Surrogate APCs 198
Conclusion 198
References 199
Chapter 9: Mechanisms and Implications of Immunodominance in CD8+ T-Cell Responses 206
Introduction: Definition of Immunodominance 207
H7a and HY: Two Model Epitopes That Lie at Opposite Ends of the Immunodominance Hierarchy in H2b Mice 208
Immunodomination Results from Competition for APC Resources 208
The Transcriptome of Anti-HY and Anti-H7a CD8+ T Cells 209
Asynchronous Differentiation of CD8+ T Cells That Recognize Dominant and Cryptic Antigens 210
T-Cell Avidity and TCR Affinity 212
Conclusion: The Role of Immunodominance 212
References 213
Chapter 10: T Regulatory Cells and Cancer Immunotherapy 218
Introduction 218
Subsets of CD4+ Treg Cells 219
Naturally Occurring Treg Cells in Mice and Humans 219
Inducible Treg Cells 220
Suppressive Mechanisms of Treg Cells 221
Inhibitory Cytokines 221
Cytolytic Pathways 222
Metabolic Dysregulation 222
Interaction with APCs 223
Evidence for Treg Cell-Mediated Suppression in Tumor Immunity 224
Mouse Tumor Models 224
Human Tumors 225
Evidence That Treg Cells Inhibit Cancer Immunotherapy 226
Strategies to Deplete/Inhibit Treg Cells to Enhance Antitumor Immunity in Mice 226
Anti-CD25 mAbs 227
Anti-GITR mAbs 227
Anti-CTLA-4 mAbs 228
Chemotherapy 228
TLRs 228
Clinical Trials to Deplete/Inhibit Treg Cells to Enhance Antitumor Immunity 229
Agents Targeting IL-2 or CD25 229
Anti-CTLA-4 mAbs 231
Other Strategies to Decrease Treg Cells 231
Conclusions 232
References 232
Chapter 11: Negative Regulators in Cancer Immunology and Immunotherapy 239
Suppressor Cells 239
Regulatory Lymphocytes 239
CD4+ as superscript in CD4+ in analogy to FOXP3 + Treg 239
Other Treg 240
Myeloid-Derived Suppressor Cells 241
Tumor-Associated Macrophages 242
Suppressive Ligands and Receptors 243
Soluble Factors 243
Prostaglandins 243
Transforming Growth Factor-b 244
Interleukin-10 245
Suppressive Cellular Receptors 245
B7-1/B7-2 Ligands and CD28/CTLA-4 Receptors 246
PD-1 Ligand and PD-1 Receptor 247
CEACAM1 Inhibitory Receptor 248
Enzymes with Immunosuppressive Function 249
Indoleamine-2,3-Dioxygenase 249
Arginase 1 and Inducible Nitric Oxide Synthase 251
Perspectives and Future Directions 254
References 255
Chapter 12: Genetically Engineered Antigen Specificity in T Cells for Adoptive Immunotherapy 260
Introduction 260
Methods of Gene Transfer to T Cells 263
T-Cell Receptor Gene Therapy 265
Engineered T-Cell Receptor Clinical Trials 267
Chimeric Antigen Receptors 269
CAR Clinical Trials 272
Considerations in T Cell Ex vivo Engineering: Gene Delivery, Choice of Antigens, and Balancing Efficacy and Safety 277
References 278
Part IV Non-Cellular Aspects of CancerImmunotherapy 287
Chapter 13: Cytokine Immunotherapy 288
Introduction 289
Cytokines as Monotherapies 294
IFN-a 294
IL-2 295
IL-12 296
IFN-g 298
GM-CSF 299
IL-10 300
TNF-a 300
Other Cytokines 301
Cytokines in Combination Therapies 303
Concluding Remarks 304
References 306
Chapter 14: Transcriptional Modulation Using Histone Deacetylase Inhibitors for Cancer Immunotherapy 313
Introduction 313
Histone Acetylation in Cancer 314
Histone Acetylation and Gene Expression 314
Classification of HDAC Enzymes and Activity in Normal and Cancer Tissues 315
Histone Modifications in Cancer 316
HDAC Inhibitors and Cancer Cell Death-Sensitivity 317
Inhibition of HDACs and Gene Expression in Cancer 317
HDAC Inhibitors and Cancer Cell Death-Sensitivity 319
Combining HDAC Inhibitors and Immunotherapy 319
HDAC Inhibitors and Immune Responses 321
Conclusions and Perspectives: Future for Cancer Immunotherapy 323
References 324
Chapter 15: Combining Cancer Vaccines with Conventional Therapies 329
Introduction 329
Immune Evasion 330
Tumor-Induced Immunosuppression 330
Selection of Tumor-Escape Variants Following Vaccination 332
Combining Surgical Resection and Vaccination 332
Neoadjuvant Immunization May Prove More Effective than Adjuvant Immunization 334
Cytotoxic Therapies and Antitumor Vaccination 335
Lymphopenia-Induced Homeostatic T-Cell Proliferation Enhances Autoimmunity 336
Chemotherapeutic Agents Can Enhance Vaccination 336
Chemotherapeutic Agents Can Augment Tumor Immunogenicity 337
Conclusions 338
References 339
Chapter 16: Combining Oncolytic Viruses with Cancer Immunotherapy 345
Introduction 345
History of Oncolytic Viruses and Their Use in Immunotherapy of Cancer 346
Induction of Antitumor Immune Responses Following Oncolytic Virus Therapy 346
Viral Oncolysates 347
Immunostimulatory Oncolytic Viruses 350
Combining Oncolytic Virotherapy and Immunotherapy 351
Vaccine Approaches 351
Immune Cells as OV Carriers 354
Future Directions 356
References 357
Chapter 17: Radiation Therapy and Cancer Treatment: From the Basics to Combination Therapies that Ignite Immunity 362
Introduction 362
Background 363
Radiation Interactions with Matter 365
Factors that Shape the Cellular Radiation Response 366
Cellular Sensing and Responses to Radiation 367
Cell Death 368
The Danger Hypothesis 368
The Tumor Microenvironment and Radiation 369
Cytokines 369
Tumor Phenotype 371
Dendritic Cells 372
Vasculature State and Leukocyte Localization 373
Cytotoxic T-Lymphocyte(CTL) Responses 373
Radiation Induced Immunosuppression: Radiation Versus Chemotherapy Coupling to Immunotherapy 375
Pre-clinical Studies 376
Dendritic Cell (DC) Therapy 376
Cytotoxic T-Cell Therapy 377
Antibody Therapy 377
Adjuvant Therapy 378
Cytokine Therapy 379
Gene Therapy 379
Clinical Trials 380
Dendritic Cell Therapy 383
Antibody Therapy 383
Adjuvant Therapy 383
Cytokine Therapy 384
Gene Therapy 385
Conclusions 386
References 387
Chapter 18: Assessing Immunotherapy Through Cellular and Molecular Imaging 394
Introduction 394
Computed Tomography 396
Ultrasound 397
Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) 399
Optical Imaging 402
Magnetic Resonance Imaging 404
Multimodal Imaging Techniques in Molecular and Cellular Imaging 406
Summary and Conclusions 407
References 408
Part V Transplantation 414
Chapter 19: Allogeneic and Autologous Transplantation Therapy of Cancer: Converging Themes 415
Transplantation: Paradigm Shift from Hematopoietic Reconstitution to T-Cell Biology 416
Antitumor Specificity 417
Immune Space 418
T-Cell Phenotype and Plasticity 421
T-Cell Differentiation Status and Apoptotic Threshold 424
Autologous and Allogeneic Immunotherapy: Therapeutic Index 425
Conclusion 429
References 429
Index 435