Targeted Cancer Immune Therapy (eBook)

Preface 5
Contents 7
Contributors 9
Part I Cytokine Immune Therapy 12
Role of IL12 Family in Regulation of Antitumor Immune Response 13
Introduction 13
Aberrant Expression of IL12 Family Member Receptors and Subunits 14
Role of IL23 in Tumor 17
Role of IL27 in Tumor 19
Role of IL12 Family in Treg Cells 22
II35 24
References 25
IL-18 in Regulation of Antitumor Immune Response and Clinical Application 29
Introduction 29
IL-18 Receptor 30
IL-18 Receptor Signal Transduction 31
IL-18 Regulation by IL-18-Binding Protein 32
IL-18 in Regulation of Antitumor Immune Response 34
IL-18 in IFNg and Th1 Response Induction 34
IL-18 in NK Cell Activation 35
IL-18 in Cytotoxic T Cell Activation 36
IL-18 as a Precancerous Factor 36
IL-18 in Tumor Growth and Immune Evasion 37
IL-18 in Tumor Angiogenesis 37
IL-18 in Tumor Metastasis 38
IL-18 as a Cancer Prognostic Marker 40
IL-18 in Cancer Therapy 42
Summary 46
References 48
Interleukin-21 and Cancer Therapy 52
Introduction 52
Preclinical Data 54
Effects of IL-21 on T Cells 54
CD4+ T Cells 54
CD8+ T Cells 55
T Regulatory Cells 56
Effects of IL-21 on NK Cells and NKT Cells 56
Effects of IL-21 on B Cells 57
Animal Tumor Studies 57
IL-21 Monotherapy 57
IL-21 Combination Therapies 59
Human Clinical Trials 59
IL-21 Monotherapy 59
IL-21 Combination Therapies 60
Future Strategies 63
Chemotherapy 63
Vaccines and Adoptive Cell Therapy 63
Immune Modulation Such as Anti-CTLA-4 or Treg Depletion 64
Summary 64
References 65
IL-24 in Regulation of Antitumor Immune Response and in Signaling 69
Introduction 69
MDA-7 as a Cytokine 71
MDA-7/IL-24 Induced Apoptosis in Cancer Cells 73
MDA-7/IL-24 Inhibits Angiogenesis in Cancer Cells 75
MDA-7/IL-24 in Tumor Metastases and Invasion 76
Clinical Evaluation of MDA-7/IL-24 77
Summary 79
References 79
IL-28 and IL-29 in Regulation of Antitumor Immune Response and Induction of Tumor Regression 83
Introduction 83
Type III IFN-Encoding Genes 85
Sources and Regulation of Type III IFNs Production 85
Type III Interferon Receptor Subunit IL-28 Receptor 87
Type III IFN-Induced Signal Transduction 89
Antitumor Effects of Type III IFN 90
Conclusions and Perspectives 99
References 100
Passive and Active Tumor Homing Cytokine Therapy 104
Introduction 104
Passive Targeting with Poly-Ethylene Glycol 106
Active Ligand Targeting with Tumor-Homing Peptides 109
Active Targeting with Tumor-Targeted Antibodies 114
Summary 117
References 118
Part II Cell-based Immune Therapy 121
New Strategies to Improve Tumor Cell Vaccine Therapy 122
Introduction 122
Increasing the Immunogenicity of Tumor Cell Vaccines 123
The Immunogenicity of Tumor Cell Vaccines 123
Transduction of Costimulatory Molecules in the Tumor Cell Vaccine 124
Transduction of GM-CSF in Tumor Cell Vaccines 125
Using Allogeneic Tumor Cell Vaccine to Improve the Immunogenicity 126
Genetic Approaches to Increase the Immunogenicity of Tumor Cell Vaccines Using Viral Vectors 127
Improving the Immunological Response of Tumor Cell Vaccines 129
Improving the Cross-Priming of CD8+ T Cells 129
Blockade of Coinhibitory Signals in Immunization 130
Enhancing the Recall Responses of Tumor-Reactive Memory T Cells 132
Summary 133
References 133
Modification of Dendritic Cells to Enhance Cancer Vaccine Potency 137
Introduction 137
Immunotherapy has Emerged as an Alternative Treatment for Cancer 137
Importance of DCs for Cancer Immunotherapy 138
Modification of the Properties of DCs 138
Strategies to Enhance Vaccine Potency by Modifying the Properties of Dendritic Cells In Vivo 142
Increasing the Number of Antigen-Expressing DCs 142
Enhancing Antigen Expression, Processing, and Presentation in DCs 143
Promoting DC Activation and Function 145
Enhancing DC and T Cell Interaction 146
Strategies to Enhance Vaccine Potency by Modifying the Properties of Dendritic Cells Ex Vivo 148
Increasing the Number of Antigen-Expressing DCs 149
Enhancing Antigen Expression, Processing, and Presentation in DCs 151
Strategies to Promote DC Activation and Function 151
Enhancing DC and T Cell Interaction 152
Clinical Trials with Ex Vivo Generated DC-Based Vaccines 153
Summary 154
References 155
Dendritic Cell Vaccines for Immunotherapy of Cancer: Challenges in Clinical Trials 162
Introduction 162
Preclinical Experience of DC-Based Cancer Vaccines and Therapies 163
Shared Antigens 165
Tumor-Associated Antigen Classification 166
Peptide-Based Vaccines 167
Protein-Loaded and Antigen-Engineered DCS 167
First Generation Clinical Trials Utilizing DC-Based Cancer Therapy 168
Limited Clinical Results for DC-Based Vaccines 170
Next Generation Clinical Trials 172
Sources of Tumor Antigen 172
Summary 173
References 173
A “Toll Bridge” for Tumor-Specific T Cells 176
Introduction 176
T Cell-Based Tumor Immunotherapy 177
T Cell Activation and Differentiation 179
Effects of Toll-Like Receptor Engagement on T cells 179
Regulation of TLR Expression on T Cell Subsets 179
Potential Impact on Clonal Expansion 181
CTL Effector Function 182
Memory T Cell Development, Persistence, and Migration 183
Modulating Regulatory CD4+ T Cell Function 184
Does TLR Engagement on T Cells Occur In Vivo? 185
When TCR and TLR Signals Collide 187
Synergistic Effects of TLR Stimulation with Anticancer Chemotherapy or Radiation Therapy 187
Exploiting TLR Signals Within T Cells to EnhanceAntitumor Immunity 188
Summary 189
References 189
Engineering Adult Stem Cells for Cancer Immunotherapy 193
Introduction 193
Stem Cell Biology 194
ESC 195
HSC 195
MSC 196
Umbilical Cord Blood Stem Cells 196
Adult Tissue-Resident Stem Cells 196
HSC for Tumor Immune Therapy-Arming Stem Cells 197
HSCT for Hematological Malignancy and Solid Tumors: GVL and GVT 197
DC-Targeted Immune Therapy from Engineered HSC 198
T Cell-Targeted Immune Therapy Using Engineered HSC 199
MSC for Immune Therapy 200
Immunotherapy Through Tumor Attraction and Cytokine Production 201
MSC in the Context of HSCT 202
Requirement and Consideration for Stem Cell Engineering for Therapeutic Use 203
Summary 204
References 205
Animal Models for Evaluating Immune Responses of Human Effector Cells In Vivo 209
Introduction 210
First Models for Human Immune Cell Engraftment 211
Improvement in Animal Models for Human Leukocyte and Stem Cell Engraftment 212
Overall Suppression of NK Activity 212
b2mnull Mice 213
The IL2Rg..c-/- Mouse 214
The NOD/SCID/IL2Rg.c-/- Mouse 214
Other Immunodeficient Mouse Models 215
Stem Cell Sources and Route of Stem Cell Delivery 215
NOD/SCID/gcnull Mice Support Human Cell Engraftment from a Variety of Stem Cell Sources 216
Routes of Human Stem Cell Injection Have Moderate Effects on Their Engraftment in NOD/SCID/gcnull Mice 216
Multilineage Differentiation of Human Stem Cells in NOD/SCID/gcnull Mice to Functional Effectors 217
Use of Humanized Mice as an Experimental Model to Evaluate Human Immune Responses 219
Functional Immune Response of Differentiated Human Immune Cells Against EBV in the Humanized Mice 220
Functional Human Immune Responses Against HIV in the Humanized Animal Models 221
Future Directions 222
Summary 223
References 223
Part III Targeted Immune Therapy 226
CD40 Stimulation and Antitumor Effects 227
Introduction 227
CD40 and Antitumor Responses: Bridging the Gap Between Innate and Adaptive Immunity 228
Anti-CD40 and Interleukin-2: Coordination of Innate and Adaptive Immunity 230
CD40 Signaling on Tumor Cells: Activation-Induced Cell Death and Cytokine Production 231
CD40 Stimulation and Vascular Effects: Another Antitumor Pathway 233
Further Considerations: Properties of Agonist CD40 Antibodies and Potential Toxicities 234
Summary 236
References 236
Immunocytokines: A Novel Approach to Cancer Immune Therapy 240
Introduction 240
Immunocytokine Structures 241
Targeting Concepts 242
Immunocytokines Containing Modified IL-2 243
Effector Cell Mechanisms 244
Evidence for Antitumor Activity in Mouse Tumor Models 246
Early Clinical Studies of Immunocytokines 247
Future Directions 250
References 253
Immune Escape: Role of Indoleamine 2,3-Dioxygenase in Tumor Tolerance 256
Introduction to Cancer Immunoediting: Immune Surveillance, Equilibrium, and Escape 256
Indoleamine 2,3-Dioxygenase 261
IDO in Human Cancer and Immune Disorders 262
IDO2: A Second Tryptophan Catabolic Enzyme 265
Cellular Pathways of Tryptophan Catabolism Signaling Regulating T Cell Immunity 266
Dendritic Cells and Immune Tolerance Mediated by IDO 269
IDO as a Target for Therapeutic Intervention 274
Concluding Comments 276
References 277
Adoptive Transfer of T-Bodies: Toward an Effective Cancer Immunotherapy 283
Introduction 284
Use of Engineered T Cells for Cancer Immunotherapy 286
Optimization of the Chimeric Receptor Function 286
Optimal Recognition of Tumor Antigens 287
Combining Costimulatory and Stimulatory Signals 287
Signaling Domains 289
Increasing the Survival and Efficacy of the T-Bodies 290
Elimination of Immunosuppressive Cells 290
Minimizing the Competition for Homeostatic Cytokines 291
Improved Availability of APC and Their Function 291
Optimizing the Safety of the Transferred T-Bodies 292
Transduction of Human T Cells: Generation of T-Bodies Toward Clinical Applications 292
T Cell Differentiation State 292
Expanding the Modified T Cell Populations 293
Summary and Conclusions 294
References 294
Targeting Toll-Like Receptor for the Induction of Immune and Antitumor Responses 298
Introduction 298
TLR4 299
TLR3 302
TLR5 304
TLR7 306
TLR9 308
Summary 310
References 311
Manipulating TNF Receptors to Enhance Tumor Immunity for the Treatment of Cancer 316
Introduction 316
Structural and Signaling Features 317
Expression 318
Antitumor Responses 319
CD27 321
GITR 322
CD134 (OX40) 323
CD137 (4-1BB) 326
Clinical Application 327
Summary 330
References 330
Index 334