Medin / Fowler Experimental and Applied Immunotherapy

1. Auflage 2010
ISBN: 978-1-60761-980-2
Verlag: Humana Press
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 442 Seiten

Immunotherapy is now recognized as an essential component of treatment for a wide variety of cancers. It is an interdisciplinary field that is critically dependent upon an improved understanding of a vast network of cross-regulatory cellular populations and a diversity of molecular effectors; it is a leading example of translational medicine with a favorable concept-to-clinical-trial timeframe of just a few years. There are many established immunotherapies already in existence, but there are exciting new cancer immunotherapies just on the horizon, which are likely to be more potent, less toxic and more cost effective than many therapies currently in use. Experimental and Applied Immunotherapy is a state-of-the-art text offering a roadmap leading to the creation of these future cancer-fighting immunotherapies. It includes essays by leading researchers that cover a wide variety of topics including T cell and non-T cell therapy, monoclonal antibody therapy, dendritic cell-based cancer vaccines, mesenchymal stromal cells, negative regulators in cancer immunology and immunotherapy, non-cellular aspects of cancer immunotherapy, the combining of cancer vaccines with conventional therapies, the combining of oncolytic viruses with cancer immunotherapy, transplantation, and more. The field of immunotherapy holds great promise that will soon come to fruition if creative investigators can bridge seemingly disparate disciplines, such as T cell therapy, gene therapy, and transplantation therapy. This text is a vital tool in the building of that bridge.

Autoren/Hrsg.

Fowler, Daniel

Medin, Jeffrey

Inhaltsverzeichnis

1;Experimental and AppliedImmunotherapy;3
1.1;Copyright;4
1.2;Foreword (Précis);5
1.3;Contents;9
1.4;Contributors;13
1.5;Part I T Cell Therapy: State-of-the-Art;19
1.5.1;Chapter 1: Extending the Use of Adoptive T Cell Immunotherapy for Infections and Cancer;20
1.5.1.1;Current State of Translational T Cell Therapy;21
1.5.1.1.1;Immunotherapy for Viral Infections Post-HSCT;21
1.5.1.1.1.1;Cytomegalovirus (CMV);21
1.5.1.1.1.2;Epstein-Barr Virus (EBV);21
1.5.1.1.1.3;Other Viruses;22
1.5.1.1.2;Immunotherapy for Virus-Associated Malignancies;22
1.5.1.1.2.1;EBV Lymphoma;22
1.5.1.1.3;Immunotherapy for Melanoma;25
1.5.1.1.3.1;T Cells Directed Against Nonviral Antigens;27
1.5.1.2;Classification of Tumor Antigens;28
1.5.1.2.1;Tumor Antigens and T-Cell Immunogenicity;28
1.5.1.2.2;Identification of Novel Tumor Antigens;28
1.5.1.2.3;Optimizing Cell Culture Protocols for Tumor-Specific CTL Generation;29
1.5.1.2.4;Antigen-Presenting Cells (APCs);29
1.5.1.2.5;Cytokines;30
1.5.1.3;Genetic Modification of T Cells;31
1.5.1.3.1;Redirecting T-cell Specificity (Genetic Modification);31
1.5.1.3.2;TCR Gene Transfer;31
1.5.1.3.3;Genetic Modification with Chimeric Antigen Receptors;34
1.5.1.3.3.1;Clinical Studies;34
1.5.1.4;Genetic Modification of T Cells to Improve in vivo Proliferation and Survival;35
1.5.1.4.1;T-cell Persistence and Survival in vivo;35
1.5.1.4.2;T-cell Sources for Genetic Modification;36
1.5.1.4.3;Gene Modification to Enhance T-Cell Proliferation;36
1.5.1.4.4;Manipulating the Infused T Cells to Counteract Tumor Evasion Strategies;37
1.5.1.4.5;Genetic Modification of T Cells to Improve Safety;38
1.5.1.4.5.1;Suicide Genes;38
1.5.1.4.5.2;Targeted Integration;39
1.5.1.4.6;Counteracting the Tumor Microenvironment;40
1.5.1.4.6.1;Nonspecific Lymphodepletion;40
1.5.1.4.6.2;Specific Treg Depletion;40
1.5.1.4.7;Scale-Up of Tumor CTL Therapy;41
1.5.1.4.8;Simplify Large-Scale CTL Production;41
1.5.1.4.9;“Off the Shelf.” CTLs Cells;42
1.5.1.4.10;Cost Effectiveness of Adoptive T-Cell Therapy versus Conventional Therapies;43
1.5.1.5;References;44
1.6;Part II Non-T Cell Therapeutic Approaches;51
1.6.1;Chapter 2: B Lymphocytes in Cancer Immunology;52
1.6.1.1;Introduction;53
1.6.1.1.1;Peripheral Human B-cell Development;53
1.6.1.1.2;B-Cell Effector States;55
1.6.1.1.3;B Cells and Cancer;57
1.6.1.1.3.1;Serology;57
1.6.1.1.3.2;Tumor-Infiltrating B Cells;58
1.6.1.1.4;B Cells and Cancer: Friends or Foes?;58
1.6.1.1.5;Evidence for a Protective Effect of B Cells in Antitumor Responses;59
1.6.1.1.6;Evidence for a Negative Effect of B Cells on Antitumor Responses;60
1.6.1.1.7;Chronic Lymphocytic Leukemia as a Paradigm for Tumor Promotion by B Cells;62
1.6.1.2;B-Cell-Directed Cancer Immunotherapy;64
1.6.1.2.1;Eliminating Negative B-Cell Effects;64
1.6.1.3;Promoting Positive B-Cell Effects;65
1.6.1.3.1;Vaccines and Recombinant Antibodies;65
1.6.1.3.2;Enhancing B-cell Activity In situ;66
1.6.1.3.3;Adoptive B-Cell Transfer;66
1.6.1.4;References;67
1.6.2;Chapter 3: Monoclonal Antibody Therapy for Cancer;73
1.6.2.1;General Considerations;73
1.6.2.1.1;Introduction;73
1.6.2.1.2;Precision and Predictability;75
1.6.2.1.3;From Hematologic to Solid Malignancies;76
1.6.2.1.4;Direct and Indirect Mechanisms of Activity;80
1.6.2.1.5;Antigen;81
1.6.2.2;Antibody Engineering;82
1.6.2.2.1;Structural Features;82
1.6.2.2.2;Chimeric, Humanized, and Fully Human mAbs;83
1.6.2.2.3;Fc Engineering;85
1.6.2.2.4;Beyond IgG;85
1.6.2.3;Clinical Performance;86
1.6.2.3.1;Overview;86
1.6.2.3.2;CD20 Targeting;87
1.6.2.3.2.1;ERBB Receptor Family Targeting;88
1.6.2.3.2.2;VEGFA Targeting;90
1.6.2.4;Outlook;91
1.6.2.5;References;92
1.6.3;Chapter 4: Natural Killer Cells for Cancer Immunotherapy;98
1.6.3.1;NK Cell Development and Identification;98
1.6.3.2;Effector Functions of NK Cells;100
1.6.3.3;NK-Target Cell Recognition and Regulation by Cell Surface Receptors;101
1.6.3.4;Inhibitory Receptors;103
1.6.3.4.1;KIRs;103
1.6.3.4.2;NKG2A/CD94 Heterodimer;104
1.6.3.5;Activating Receptors;104
1.6.3.5.1;NKG2D;104
1.6.3.5.2;Natural Cytotoxicity Receptors (NCR);105
1.6.3.5.3;CD16 (Fcg.RIII);105
1.6.3.5.4;DNAM-1 (CD226);105
1.6.3.6;Extrinsic Regulation of NK Cells;106
1.6.3.7;Role of NK Cells in Cancer;106
1.6.3.8;Clinical use of NK Cells;107
1.6.3.8.1;Adoptive Immunotherapy;107
1.6.3.9;Strategies that Target NK Cells;110
1.6.3.9.1;Antibody Therapies;110
1.6.3.9.2;Engaging Activating Signals;111
1.6.3.9.3;Blocking Inhibitory Signals;112
1.6.3.9.4;Chemotherapeutic Drugs;112
1.6.3.10;Conclusions and Future Challenges;112
1.6.3.11;References;113
1.6.4;Chapter 5: Dendritic Cell-Based Cancer Vaccines: Practical Considerations;119
1.6.4.1;Introduction;119
1.6.4.1.1;Dendritic Cell Biology;120
1.6.4.1.2;Autologous Clinical Vaccine Trials;122
1.6.4.2;Clinical Dendritic Cell Studies: Issues Facing the Field;122
1.6.4.2.1;DC Source and Vaccine Manufacture;122
1.6.4.3;Antigen Loading of DCs;126
1.6.4.3.1;Route of Administration;128
1.6.4.3.2;Cancer Type: Susceptibility to DC Therapy;129
1.6.4.4;Summary;130
1.6.4.4.1;Issues in Clinical Trial Methodology;130
1.6.4.4.2;Standardization of DC Preparation;131
1.6.4.4.3;Immunological Parameters;131
1.6.4.4.4;Combination Therapy;132
1.6.4.4.5;Future Directions;132
1.6.4.5;References;133
1.6.5;Chapter 6: Mesenchymal Stromal Cells: An Emerging Cell-Based Pharmaceutical;139
1.6.5.1;Introduction and Classification;140
1.6.5.2;Physiological Functions of MSC;141
1.6.5.2.1;MSC and Hematopoiesis;141
1.6.5.2.1.1;PBSC Transplantation;141
1.6.5.2.2;MSC Homing;142
1.6.5.2.3;Osteogenesis Imperfecta;142
1.6.5.2.4;Myocardial Infarction;143
1.6.5.3;MSC Immuno-regulatory Functions;144
1.6.5.3.1;Background MSC Immune Characteristics;144
1.6.5.3.2;MSC and Immunosuppression: Direct versus Indirect T-Cell Inhibition;144
1.6.5.3.3;Direct T-Cell Immunosuppression;145
1.6.5.3.4;Indirect T-Cell Immunosuppression;145
1.6.5.3.4.1;Via Macrophages;145
1.6.5.3.4.2;Via DC;147
1.6.5.3.5;B Cells;147
1.6.5.3.5.1;Immunosuppressive Properties of MSC for Immunotherapy;148
1.6.5.3.5.2;MSC for the Prevention and Treatment of Steroid Refractory Acute GVHD;148
1.6.5.3.5.3;MSC for the Treatment of Arthritic Diseases;151
1.6.5.3.5.4;MSC for the Treatment of Multiple Sclerosis;151
1.6.5.3.5.5;MSC and Organ Transplantation;152
1.6.5.3.6;Immune Activation by MSC;152
1.6.5.3.6.1;Immune Recognition;152
1.6.5.3.6.2;MSC are Conditional APC;152
1.6.5.3.7;Future Objectives Regarding MSC and Immunotherapy;153
1.6.5.3.8;MSC and Cancer;154
1.6.5.4;Concluding Remarks;155
1.6.5.5;References;155
1.7;Part III T Cell Therapeutic Approaches;161
1.7.1;Chapter 7: Tumor-Specific Mutations as Targets for Cancer Immunotherapy;162
1.7.1.1;A Brief Overview of Cancer Genomics;163
1.7.1.2;Basics of Cellular Immunology and the Potential for Immune Recognition of Tumor-Specific Mutations;165
1.7.1.3;Evidence of Naturally Occurring Cellular Immunity Against Tumor-Specific Mutations;168
1.7.1.3.1;Clinical Immunotherapy Trials That Have Targeted Tumor-Specific Mutations;169
1.7.1.3.1.1;Ras;169
1.7.1.3.1.2;BCR-ABL;174
1.7.1.4;Roadmap for the Field;176
1.7.1.5;Summary;178
1.7.1.6;References;178
1.7.2;Chapter 8: Counteracting Subversion of MHC Class II Antigen Presentation by Tumors;184
1.7.2.1;Tumors and the Immune System;184
1.7.2.1.1;Role of Adaptive CD4+ T-Cell Responses in Tumor Eradication;186
1.7.2.1.2;Tumor Cells as APCs;187
1.7.2.1.3;Why Does the Antitumor T-Cell Response Often Prove Defective?;188
1.7.2.2;Subversion of MHC II Antigen Presentation in Tumors;188
1.7.2.2.1;Overview of the MHC-II Antigen Presentation Pathway;188
1.7.2.2.2;Patterns of MHC Class II Expression in Tumor Cells;190
1.7.2.2.3;Patterns of Ii Expression in Tumor Cells;192
1.7.2.2.4;Patterns of HLA-DM and -DO Expression in Tumors;192
1.7.2.2.5;Modulation of MHC II Accessory Molecules in Tumors;193
1.7.2.2.6;Counteracting Subversion of Antigen Presentation;194
1.7.2.2.7;Discovery of Novel TAAs and T-Cell Epitopes;195
1.7.2.2.8;Cellular Vaccines;195
1.7.2.2.8.1;Tumor Vaccines;195
1.7.2.2.8.2;DC Vaccines;196
1.7.2.2.8.3;B-Cell Vaccines;198
1.7.2.2.8.4;Surrogate APCs;198
1.7.2.3;Conclusion;198
1.7.2.4;References;199
1.7.3;Chapter 9: Mechanisms and Implications of Immunodominance in CD8+ T-Cell Responses;206
1.7.3.1;Introduction: Definition of Immunodominance;207
1.7.3.1.1;H7a and HY: Two Model Epitopes That Lie at Opposite Ends of the Immunodominance Hierarchy in H2b Mice;208
1.7.3.1.2;Immunodomination Results from Competition for APC Resources;208
1.7.3.1.3;The Transcriptome of Anti-HY and Anti-H7a CD8+ T Cells;209
1.7.3.1.4;Asynchronous Differentiation of CD8+ T Cells That Recognize Dominant and Cryptic Antigens;210
1.7.3.1.5;T-Cell Avidity and TCR Affinity;212
1.7.3.2;Conclusion: The Role of Immunodominance;212
1.7.3.3;References;213
1.7.4;Chapter 10: T Regulatory Cells and Cancer Immunotherapy;218
1.7.4.1;Introduction;218
1.7.4.1.1;Subsets of CD4+ Treg Cells;219
1.7.4.1.1.1;Naturally Occurring Treg Cells in Mice and Humans;219
1.7.4.1.1.2;Inducible Treg Cells;220
1.7.4.1.2;Suppressive Mechanisms of Treg Cells;221
1.7.4.1.2.1;Inhibitory Cytokines;221
1.7.4.1.2.2;Cytolytic Pathways;222
1.7.4.1.2.3;Metabolic Dysregulation;222
1.7.4.1.2.4;Interaction with APCs;223
1.7.4.1.3;Evidence for Treg Cell-Mediated Suppression in Tumor Immunity;224
1.7.4.1.3.1;Mouse Tumor Models;224
1.7.4.1.3.2;Human Tumors;225
1.7.4.1.4;Evidence That Treg Cells Inhibit Cancer Immunotherapy;226
1.7.4.1.5;Strategies to Deplete/Inhibit Treg Cells to Enhance Antitumor Immunity in Mice;226
1.7.4.1.5.1;Anti-CD25 mAbs;227
1.7.4.1.5.2;Anti-GITR mAbs;227
1.7.4.1.5.3;Anti-CTLA-4 mAbs;228
1.7.4.1.5.4;Chemotherapy;228
1.7.4.1.5.5;TLRs;228
1.7.4.1.6;Clinical Trials to Deplete/Inhibit Treg Cells to Enhance Antitumor Immunity;229
1.7.4.1.6.1;Agents Targeting IL-2 or CD25;229
1.7.4.1.6.2;Anti-CTLA-4 mAbs;231
1.7.4.1.6.3;Other Strategies to Decrease Treg Cells;231
1.7.4.2;Conclusions;232
1.7.4.3;References;232
1.7.5;Chapter 11: Negative Regulators in Cancer Immunology and Immunotherapy;239
1.7.5.1;Suppressor Cells;239
1.7.5.1.1;Regulatory Lymphocytes;239
1.7.5.1.1.1;CD4+ as superscript in CD4+ in analogy to FOXP3 + Treg;239
1.7.5.1.1.2;Other Treg;240
1.7.5.1.2;Myeloid-Derived Suppressor Cells;241
1.7.5.1.3;Tumor-Associated Macrophages;242
1.7.5.2;Suppressive Ligands and Receptors;243
1.7.5.2.1;Soluble Factors;243
1.7.5.2.2;Prostaglandins;243
1.7.5.2.3;Transforming Growth Factor-b;244
1.7.5.2.4;Interleukin-10;245
1.7.5.2.5;Suppressive Cellular Receptors;245
1.7.5.2.6;B7-1/B7-2 Ligands and CD28/CTLA-4 Receptors;246
1.7.5.2.7;PD-1 Ligand and PD-1 Receptor;247
1.7.5.2.8;CEACAM1 Inhibitory Receptor;248
1.7.5.3;Enzymes with Immunosuppressive Function;249
1.7.5.3.1;Indoleamine-2,3-Dioxygenase;249
1.7.5.3.2;Arginase 1 and Inducible Nitric Oxide Synthase;251
1.7.5.4;Perspectives and Future Directions;254
1.7.5.5;References;255
1.7.6;Chapter 12: Genetically Engineered Antigen Specificity in T Cells for Adoptive Immunotherapy;260
1.7.6.1;Introduction;260
1.7.6.2;Methods of Gene Transfer to T Cells;263
1.7.6.2.1;T-Cell Receptor Gene Therapy;265
1.7.6.3;Engineered T-Cell Receptor Clinical Trials;267
1.7.6.4;Chimeric Antigen Receptors;269
1.7.6.5;CAR Clinical Trials;272
1.7.6.6;Considerations in T Cell Ex vivo Engineering: Gene Delivery, Choice of Antigens, and Balancing Efficacy and Safety;277
1.7.6.7;References;278
1.8;Part IV Non-Cellular Aspects of CancerImmunotherapy;287
1.8.1;Chapter 13: Cytokine Immunotherapy;288
1.8.1.1;Introduction;289
1.8.1.2;Cytokines as Monotherapies;294
1.8.1.2.1;IFN-a;294
1.8.1.2.2;IL-2;295
1.8.1.2.3;IL-12;296
1.8.1.2.4;IFN-g;298
1.8.1.2.5;GM-CSF;299
1.8.1.2.6;IL-10;300
1.8.1.2.7;TNF-a;300
1.8.1.2.8;Other Cytokines;301
1.8.1.3;Cytokines in Combination Therapies;303
1.8.1.4;Concluding Remarks;304
1.8.1.5;References;306
1.8.2;Chapter 14: Transcriptional Modulation Using Histone Deacetylase Inhibitors for Cancer Immunotherapy;313
1.8.2.1;Introduction;313
1.8.2.2;Histone Acetylation in Cancer;314
1.8.2.2.1;Histone Acetylation and Gene Expression;314
1.8.2.2.2;Classification of HDAC Enzymes and Activity in Normal and Cancer Tissues;315
1.8.2.2.3;Histone Modifications in Cancer;316
1.8.2.3;HDAC Inhibitors and Cancer Cell Death-Sensitivity;317
1.8.2.3.1;Inhibition of HDACs and Gene Expression in Cancer;317
1.8.2.3.2;HDAC Inhibitors and Cancer Cell Death-Sensitivity;319
1.8.2.3.3;Combining HDAC Inhibitors and Immunotherapy;319
1.8.2.4;HDAC Inhibitors and Immune Responses;321
1.8.2.5;Conclusions and Perspectives: Future for Cancer Immunotherapy;323
1.8.2.6;References;324
1.8.3;Chapter 15: Combining Cancer Vaccines with Conventional Therapies;329
1.8.3.1;Introduction;329
1.8.3.2;Immune Evasion;330
1.8.3.2.1;Tumor-Induced Immunosuppression;330
1.8.3.2.2;Selection of Tumor-Escape Variants Following Vaccination;332
1.8.3.2.3;Combining Surgical Resection and Vaccination;332
1.8.3.2.4;Neoadjuvant Immunization May Prove More Effective than Adjuvant Immunization;334
1.8.3.2.5;Cytotoxic Therapies and Antitumor Vaccination;335
1.8.3.2.5.1;Lymphopenia-Induced Homeostatic T-Cell Proliferation Enhances Autoimmunity;336
1.8.3.2.5.2;Chemotherapeutic Agents Can Enhance Vaccination;336
1.8.3.2.5.3;Chemotherapeutic Agents Can Augment Tumor Immunogenicity;337
1.8.3.3;Conclusions;338
1.8.3.4;References;339
1.8.4;Chapter 16: Combining Oncolytic Viruses with Cancer Immunotherapy;345
1.8.4.1;Introduction;345
1.8.4.2;History of Oncolytic Viruses and Their Use in Immunotherapy of Cancer;346
1.8.4.2.1;Induction of Antitumor Immune Responses Following Oncolytic Virus Therapy;346
1.8.4.2.2;Viral Oncolysates;347
1.8.4.2.3;Immunostimulatory Oncolytic Viruses;350
1.8.4.3;Combining Oncolytic Virotherapy and Immunotherapy;351
1.8.4.3.1;Vaccine Approaches;351
1.8.4.3.2;Immune Cells as OV Carriers;354
1.8.4.4;Future Directions;356
1.8.4.5;References;357
1.8.5;Chapter 17: Radiation Therapy and Cancer Treatment: From the Basics to Combination Therapies that Ignite Immunity;362
1.8.5.1;Introduction;362
1.8.5.2;Background;363
1.8.5.2.1;Radiation Interactions with Matter;365
1.8.5.2.2;Factors that Shape the Cellular Radiation Response;366
1.8.5.2.3;Cellular Sensing and Responses to Radiation;367
1.8.5.3;Cell Death;368
1.8.5.3.1;The Danger Hypothesis;368
1.8.5.4;The Tumor Microenvironment and Radiation;369
1.8.5.4.1;Cytokines;369
1.8.5.4.2;Tumor Phenotype;371
1.8.5.4.3;Dendritic Cells;372
1.8.5.4.4;Vasculature State and Leukocyte Localization;373
1.8.5.4.5;Cytotoxic T-Lymphocyte(CTL) Responses;373
1.8.5.5;Radiation Induced Immunosuppression: Radiation Versus Chemotherapy Coupling to Immunotherapy;375
1.8.5.6;Pre-clinical Studies;376
1.8.5.6.1;Dendritic Cell (DC) Therapy;376
1.8.5.6.2;Cytotoxic T-Cell Therapy;377
1.8.5.6.3;Antibody Therapy;377
1.8.5.6.3.1;Adjuvant Therapy;378
1.8.5.6.3.2;Cytokine Therapy;379
1.8.5.6.3.3;Gene Therapy;379
1.8.5.7;Clinical Trials;380
1.8.5.7.1;Dendritic Cell Therapy;383
1.8.5.7.2;Antibody Therapy;383
1.8.5.7.3;Adjuvant Therapy;383
1.8.5.7.4;Cytokine Therapy;384
1.8.5.7.5;Gene Therapy;385
1.8.5.8;Conclusions;386
1.8.5.9;References;387
1.8.6;Chapter 18: Assessing Immunotherapy Through Cellular and Molecular Imaging;394
1.8.6.1;Introduction;394
1.8.6.1.1;Computed Tomography;396
1.8.6.1.2;Ultrasound;397
1.8.6.1.3;Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT);399
1.8.6.1.4;Optical Imaging;402
1.8.6.2;Magnetic Resonance Imaging;404
1.8.6.3;Multimodal Imaging Techniques in Molecular and Cellular Imaging;406
1.8.6.4;Summary and Conclusions;407
1.8.6.5;References;408
1.9;Part V Transplantation;414
1.9.1;Chapter 19: Allogeneic and Autologous Transplantation Therapy of Cancer: Converging Themes;415
1.9.1.1;Transplantation: Paradigm Shift from Hematopoietic Reconstitution to T-Cell Biology;416
1.9.1.2;Antitumor Specificity;417
1.9.1.3;Immune Space;418
1.9.1.4;T-Cell Phenotype and Plasticity;421
1.9.1.5;T-Cell Differentiation Status and Apoptotic Threshold;424
1.9.1.6;Autologous and Allogeneic Immunotherapy: Therapeutic Index;425
1.9.1.7;Conclusion;429
1.9.1.8;References;429
1.10;Index;435