Cancer Immunology and Immunotherapy (eBook)

Preface 6
References 7
Contents 8
Contributors 10
Immune Infiltration in Human Cancer: Prognostic Significance and Disease Control 16
1 Introduction 17
2 ``In Situ´´ Immune Contexture, the Strongest Prognostic Factor for Recurrence and Overall Survival: The Case of Colorectal Cancer 19
3 Induction of Functionally Active Tertiary Lymphoid Structures in the Vicinity of Tumoral Beds as Potential Sites of ``In Situ Immune Reactions: The Example ofLung Carcinoma 23
4 Subversion of Innate Immunity Receptors: Stimulation of Toll Like Receptors on Lung Carcinoma Cells Modulates Cell Survival and Response to Chemotherapy 26
5 ``Paradoxical´´ Control of Inflammation Influences Clinical Outcome in Head and Neck Cancer 28
6 The Immune Reaction in a Tumor Developing in an Immuno-Priviledged Site: The Case of Primary Intraocular Lymphoma 31
7 Conclusions 33
References 34
Subversion and Coercion: The Art of Redirecting Tumor Immune Surveillance 40
1 Introduction 41
2 The Inflammatory Trio: TNF-a, TGF-beta, IL-6 43
3 The Local Trigger: IL-23 and IL-12 Balance in the Tumor Microenvironment 45
4 Feeding the Inflammatory Niche: Adaptive T Cell Responses Fostering the Tumor 46
5 Turning Foes into Friends, CD8+ T Cells Lose Their Teeth 47
6 Inflammatory Control at the Tumor Site 48
7 Conclusions 50
References 51
STAT3: A Target to Enhance Antitumor Immune Response 55
1 Introduction 56
2 Stat3-Mediated Immune Suppression 57
2.1 Inhibition of the Th1 Immune Response 57
2.2 Relevant Immunologic Signaling Pathways 59
2.3 Role in Myeloid Derived Suppressor Cells 60
2.4 Role in Regulatory T-Cells 61
3 Therapeutic Relevance 62
3.1 Genetic Evidence and Potential Toxicity 63
3.2 JAK Inhibitors 63
3.3 Other Oncogenic Kinase Inhibitors 64
3.4 RTK Inhibitors 65
3.5 siRNA 66
4 Concluding Remarks 67
References 67
Biology and Clinical Observations of Regulatory T Cells in Cancer Immunology 74
1 Introduction 76
2 Treg Lineage and Development 76
3 Treg Subsets 77
3.1 Cell Surface Markers of Mouse Tregs 77
3.2 Cell Surface Markers of Human Tregs 78
3.3 Toll Like Receptors Expressed by Tregs 79
3.4 Functional Subsets of Tregs 79
3.5 Treg-Derived Malignancies 80
4 Mechanisms of Treg-Mediated Immune Suppression in Cancer 80
4.1 Immunosuppressive Cytokines and Factors 81
4.2 Suppression by Direct Cell-Cell Contact 81
4.3 Treg-Mediated Cytotoxicity 82
5 Clinical Observations of the Association of Tregs with Cancer 82
6 Modification of Treg Biology as Cancer Immunotherapy 90
6.1 The Cellular Microenvironment 90
6.2 Strategies to Modulate Treg Number and Function 92
6.3 Attenuating Treg Function 93
7 Conclusions 96
References 96
Concepts and Ways to Amplify the Antitumor Immune Response 109
1 Introduction 110
2 Pharmacology of Tumor Cell-Immune Cell Interactions 112
3 Tumor Cell Development and Its Danger Signals 113
3.1 Neoplastic Cells 114
3.2 Chronic Inflammation 115
3.3 Stroma 117
4 Expression and Presentation of Tumor Antigens 117
5 Mouse Models of Cancer 119
5.1 The LCMV Model to Study the Regulation of MHCI Expression 119
5.2 The L12R4 Vaccination Model 121
5.3 The SR/CR Mouse Model 122
6 Cellular and Molecular Regulation of Tumor Immunity 125
7 Discussion 129
References 134
Angiogenesis and the Tumor Vasculature as Antitumor Immune Modulators: The Role of Vascular Endothelial Growth Factor and Endothelin 141
1 Introduction 142
2 Angiogenesis and Cancer 143
3 Vascular Endothelial Growth Factor 144
4 Direct Effects of VEGF on Leukocytes 145
4.1 Dendritic Cell Defects in Cancer Patients and Mouse Models: A Role for VEGF 145
4.2 Effects of VEGF on T Cells 147
5 VEGF, the Tumor Vascular Endothelium, and Immune Evasion 149
5.1 The Vascular Endothelium 149
5.2 VEGF and Adhesion Molecule Expression 149
6 The Tumor Endothelium and VEGF Crosstalk: A Role for the Endothelin System 150
6.1 The Endothelin System 150
6.2 Endothelin and Tumor Angiogenesis 151
6.3 ETBR and the Tumor Endothelial Barrier to T Cell Homing 152
7 Concluding Statements 153
References 154
Adoptive Cellular Therapy 161
1 Introduction 162
2 Finding the Right Tool for the Job 163
3 Considerations of Cell Culture Technology 165
3.1 General Approaches for Cell Manufacturing 166
3.2 Artificial APC 167
3.3 Moving to the Dark Side: Culture Systems for Tregs 168
4 Engineering T Cells 169
4.1 Introduction of Transgenic TCRs 169
4.2 Creation of MHC-Independent T Cells with Chimeric Antigen Receptors 170
4.3 Issues Facing the Field with Gene-Modified ACT 171
5 Post-Transplant ACT 172
5.1 ACT for Hematologic Malignancies 174
5.2 ACT for Neuroblastoma 176
6 Concluding Remarks 177
References 178
Dendritic Cell Subsets as Vectors and Targets for Improved Cancer Therapy 185
1 Introduction 186
2 Dendritic Cells 187
2.1 Human Dendritic Cell Subsets 187
2.1.1 Dermal DCs, Antibody Responses and IL-12 187
2.1.2 LCs and CD8+ T Cell Responses 189
2.1.3 Plasmacytoid DCs 189
2.2 DCs in Tumor Environment 190
3 Dendritic Cells in Vaccination Against Cancer 192
3.1 Outcomes of Current DC Vaccination Trials 192
3.2 The Quality of Elicited Antigen-Specific Immune Responses 192
4 Building on Dendritic Cell Subsets to Improve Cancer Vaccines 193
4.1 Optimal DCs 193
4.2 ``Ideal´´ Antigens 194
4.3 Combining DC Vaccines with Other Therapies 195
5 Concluding Remarks 197
References 198
Identification of Human Idiotype-Specific T Cells in Lymphoma and Myeloma 205
1 Introduction 206
2 Idiotype Protein as a Tumor Antigen: Discovery Research 206
3 Clinical Investigational New Drug Vaccine Development 207
4 Pivotal Phase III Trials 207
5 Idiotype-Specific T Cell Immunity Elicited by Idiotype Vaccination in Preclinical Models 209
6 Human T Cell Epitopes Identified in Lymphoma-Derived Idiotype Proteins 211
7 Ig Light-Chain as a Source of Idiotype Peptide Recognized by Human T Cells 213
8 Future Directions for Idiotype-Specific T Cell Immunotherapy 216
References 218
Modulation of CTLA-4 and GITR for Cancer Immunotherapy 223
1 Introduction 224
2 CTLA-4 Preclinical Data 225
2.1 CTLA-4: A ``Brake´´ on T Cell Activation 226
2.1.1 Cell Intrinsic Suppression 227
2.1.2 Cell Extrinsic Suppression 227
2.2 Preclinical Studies Using CTLA-4 Blocking Antibodies 229
2.2.1 Monotherapy 229
2.2.2 CTLA-4 and Active/Passive Immunization 229
2.2.3 CTLA-4 and Chemotherapy/Radiotherapy/Tumor Ablation 230
2.2.4 CTLA-4 and Other Immunostimulatory Strategies 230
3 GITR Preclinical 231
3.1 GITR: ``Accelerator´´ of Effector Function 232
3.2 Preclinical Studies Using GITR Agonist Antibody 232
3.2.1 Monotherapy 233
3.2.2 GITR and Active Immunization 233
4 Clinical Experiences with CTLA-4 Blockade 234
4.1 CTLA-4 Monotherapy 235
4.2 Postsurgical Adjuvant Therapy 237
4.3 Combinations 238
4.4 Tremelimumab 238
4.5 Immune Related Adverse Effects 239
4.6 Novel Criteria for Antitumor Response to Ipilimumab and Increased Duration of Response 239
4.7 Other Malignancies 240
5 From Clinical Trials, Back to the Bench 241
5.1 Monitoring Antigen-Specific CD4+ and CD8+ T Cell Activity and Polyfunctionality 241
5.2 Cellular Phenotype Analysis: ICOS, Foxp3, HLA-DR and IDO 242
5.3 ICOS 243
5.4 Foxp3 243
5.5 HLA-DR 243
5.6 IDO 244
5.7 Antibody Responses 244
5.8 The ``Immunogram´´: A Tool to Synthesize Immune Monitoring 245
6 Future Directions 245
References 248
Immunobiology of Cancer Therapies Targeting CD137 and B7-H1/PD-1 Cosignal Pathways 257
1 Introduction 258
2 The Costimulatory CD137 Signaling Pathway 260
2.1 The Expression of CD137L and CD137 260
2.2 Role of CD137 Cosignaling in Effector/Memory T Cells 261
3 Strategies to Augment Tumor Immunity by Stimulating CD137 262
3.1 Tumor Therapy with Agonist Anti-CD137 Antibody 262
3.2 Whole Cell Vaccines with Capacity to Stimulate CD137 264
3.3 Adoptive Transfer of T Cells with CD137 Costimulation 265
4 The Coinhibitory B7-H1/PD-1 Signaling Pathway 266
4.1 Expression of B7-H1, B7-DC and PD-1 266
4.2 Complex Interactions Among B7-H1, B7-DC, B7-1, PD-1, and Possible Additional Binding Partners 267
4.3 B7-H1/PD-1 Interaction in the Suppression of Immune Responses 268
5 Manipulation of B7-H1/PD-1 Pathway in Tumor Immunotherapy 269
5.1 B7-H1/PD-1 Pathway in the Evasion of Tumor Immunity 269
5.2 Blocking B7-H1/PD-1 Pathway in Cancer Therapy 271
References 272
LAG-3 in Cancer Immunotherapy 280
1 Structural Aspects of LAG-3 281
1.1 Basic Structure 281
1.2 LAG-3 Expression 281
1.3 Binding of Class II MHC 282
1.4 Localization of LAG-3 in T Cells 283
2 LAG-3 Function 283
2.1 Role in CD4 T Cell Function and Expansion 283
2.2 Role of LAG-3 on Regulatory T Cells 284
2.3 Role of LAG-3 on CD8 T Cells 284
2.4 LAG-3 Mechanism of Action 285
3 LAG-3 in Cancer Immunotherapy 286
3.1 Preclinical Studies 286
3.2 Clinical Studies 286
4 Conclusions 287
References 288
Immunologically Active Biomaterials for Cancer Therapy 290
1 The Challenge of Cancer Immunotherapy 291
2 Sources and Inspiration for Biomaterials 293
2.1 Raw Materials 293
2.2 Controlled Delivery and Cell Targeting 294
2.3 Synthetic ECMs 295
3 Antigen Delivery and DC Targeting 296
4 Adjuvant Materials 299
5 Three-Dimensional Niches That Regulate Immune Responses In Situ 302
6 Conclusions and Future Prospects 303
References 304
Erratum: Identification of Human Idiotype-Specific T Cells in Lymphoma and Myeloma 309
Index 310