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Tumor-associated antigens : identification, characterization, and clinical applications / edited by Olivier Gires and Barbara Seliger. — Weinheim : Wiley-VCH, c2009. – (64.84/T925t) |
Contents
Contents
List of Contributors XV
Part One Tumor-associated Antigens (TAAs): Subclasses of TAAs 1
1 T Cell Antigens in Cancer 3
1.1 Introduction 3
1.2 Generation of T-cell Epitopes 4
1.2.1 Subclasses of Tumor-associated T-cell Antigens 5
1.2.1.1 Unique Tumor Antigens 6
1.2.1.2 Cancer Testis Antigens 6
1.2.1.3 Differentiation Antigens 7
1.2.1.4 Overexpressed Antigens 7
1.3 Identification of T-cell Antigens and their Epitopes 8
1.3.1 T-cell Antigens for Cancer Immunotherapy - How are Candidates Selected?
1.4 Conclusions 12
References 12
2 Human Tumor Antigens as Targets of Immunosurveillance and Candidates for Cancer Vaccines 23
2.1 Introduction 23
2.2 Tumor Antigen Classes 24
2.2.1 Oncofetal Antigens 24
2.2.2 Oncogenes as Tumor Antigens 25
2.2.3 Overexpressed Normal Molecules as Tumor Antigens 26
2.2.4 Cancer-Testis (CT) Antigens 26
2.2.5 Minor Histocompatibility Antigens (mHAgs) as Tumor Antigens 27
2.2.6 Human Melanoma Antigens 28
2.2.7 Human Glioma Antigens and Immunosurveillance in the CNS 29
2.2.8 Heat Shock Proteins， Efficient Carriers of Tumor Antigens 30
2.2.9 Dendritic Cells， Efficient Cross-presenters of Tumor Antigens 31
2.2.10 Spontaneous and Vaccine-induced Immunity and the Tumor Microenvironment
2.3 Summary 34
References 34
Part Two Methods to Detect TAAs 45
3 Humoral Immune Responses against Cancer Antigens: Serological Identification Methods. Part I: SEREX 47
3.1 Introduction 47
3.2 The SEREX Approach 48
3.2.1 Identification of Human Tumor Antigens by SEREX 49
3.2.2 Specificity of Human Tumor Antigens 50
3.2.2.1 Shared Tumor Antigens 50
3.2.2.2 Differentiation Antigens 51
3.2.2.3 Antigens Encoded by Mutated Genes 51
3.2.2.4 Viral Genes 52
3.2.2.5 Overexpressed Genes 52
3.2.2.6 Amplified Genes 52
3.2.2.7 Splice Variants of Known Genes 52
3.2.2.8 Cancer-related Autoantigens 52
3.2.2.9 Non-cancer-related Autoantigens 52
3.2.2.10 Products of Underexpressed Genes 53
3.2.3 Significance of Antibodies against SEREX Antigens 53
3.2.4 Reverse T Cell Immunology 53
3.2.5 Functional Significance of Human Tumor Antigens 54
3.2.6 The Human Cancer Immunome 54
3.2.7 Perspectives for Vaccine Development 56
Conclusions 57
References 58
4 Humoral Immune Responses against Cancer Antigens: Serologica Identification Methods. Part I1: Proteomex and AMIDA 63
4.1 Introduction 63
4.1.1 A Humoral Response against Self-antigens: The Notion of Tumor-associated Antigens 64
4.2 Implementation of Serum Antibodies: Serological Screening Technologies
4.2.1 PROTEOMEX， alias SERPA and SPEARS 66
4.2.1.1 PROTEOMEX Technology and its 'Pros' and 'Cons' 67
4.2.1.2 Candidate Biomarkers Identified by PROTEOMEX 67
4.2.1.3 Implementation of Candidate Biomarkers in the Clinic 68
4.2.2 AMIDA 68
4.2.2.1 Autologous AMIDA 69
4.2.2.2 Allo-AMIDA 69
4.2.3 Advantages and Disadvantages of AMIDA 71
4.3 AMIDA Antigens and Clinical Application 71
4.3.1 Diagnostic TAAs Detected with AMIDA Screening 71
4.3.2 Therapeutic Markers 72
4.4 Conclusions 72
References 73
5 cDNA and Microarray-based Technologies 79
5.1 Introduction 79
5.2 Technical Aspects 80
5.2.1 Handling of Samples and the Need for Consistent Messenger RNA Amplification
5.2.1.1 Collection of Source Material and RNA Isolation 82
5.2.1.2 Single Strand cDNA Synthesis 83
5.2.1.3 Double-stranded cDNA (ds-cDNA) Synthesis 84
5.2.2 RNA Amplifications 85
5.2.2.1 Linear Amplification 85
5.2.2.2 PCR-based Exponential Amplification 86
5.2.2.3 Target Labeling for cDNA Microarray using Amplified RNA 88
5.2.2.4 Bioinformatics Tools 89
5.2.2.5 Limitations of Transcriptional Profiling 90
5.2.2.6 Usefulness of Transcriptional Profiling for Antigen Discovery and the Understanding of Tumor-Host Interactions 90
5.3 Summary 93
References 93
6 Detection and Identification of TAA by SELDI-TOF 103
6.1 Introduction 103
6.2 SELDI (ProteinChip) Technology 104
6.2.1 The Procedural Method 104
6.2.2 SELDI-MS in TAA Identification 106
6.2.2.1 Tumor Samples 106
6.2.2.2 Body Fluids 106VIII Contents
6.2.2.3 SELDI-MS TAAs and Clinical Potential
6.3 Conclusions and Future Perspectives
References 108
Part Three TAAs and Their Usefulness 113
7 Tumor-associated Antigens in Childhood Cancer 115
7.1 Introduction to Childhood Cancer 115
7.1.1 Incidence， Etiology and Types of Cancer in Children 115
7.1.2 Cure Rates， Treatment Failure and Toxicity 115
7.2 TAA for Pediatric Cancer Therapy 116
7.2.1 Potential Clinical Impact of Childhood TAA and Strategies for their Identification 116
7.2.2 TAA in Childhood Leukemia 117
7.2.3 TAA in Childhood Brain Tumors 119
7.2.4 TAA in Childhood Lymphoma 121
7.2.5 TAA in Pediatric Neuroblastoma 122
7.2.6 TAA in Rhabdomyosarcoma and other Soft Tissue Sarcomas 124
7.2.7 TAA in Osteosarcoma 125
7.2.8 TAA in Tumors of the Ewing Family 126
7.2.9 TAA in Wilms' Tumor 127
7.3 Conclusion 128
References 129
8 Epigenetically-regulated Therapeutic Tumor-associated Antigens 143
8.1 Introduction 143
8.2 Epigenetics 144
8.2.1 DNA Methylation 144
8.2.2 Histone Post-translational Modifications 145
8.3 TAA 146
8.3.1 Classification of TAA 146
8.3.2 Epigenetically-regulated TAA 146
8.3.2.1 HMW-MAA 146
8.3.2.2 Mucins 147
8.3.2.3 CTA 148
8.4 Perspectives and Conclusion 153
References 153
9 Cancer Testis Antigens 161
9.1 Introduction 161
9.2 Definitions and Classification 162
9.3 Tissue Distribution 163
9.3.1 Normal tissues 163
9.3.2 Tumors 163
9.4 Function 164
9.5 Immunology 166
9.6 Clinical Trials 167
9.7 Conclusions 172
References 173
10 Rationale for Treatment of Colorectal Cancer with EpCAM Targeting Therapeutics 179
10.1 Introduction 179
10.2 EpCAM Expression in Colorectal Cancer 181
10.2.1 Frequent and High Level Expression of EpCAM in Primary Tumors of Colon Cancer 181
10.2.2 EpCAM Expression on Colon Cancer Metastases 183
10.2.3 EpCAM Expression on Circulating Colon Cancer Cells 184
10.2.4 EpCAM Expression on Colon Cancer Stem Cells 184
10.2.5 EpCAM Expression on Human Colon Cancer Cell Lines 185
10.3 EpCAM-directed Therapeutic Approaches 185
10.3.1 Clinical Results with Anti-EpCAM Murine Antibody Edrecolomab in Stage II and III CRC 185
10.3.2 Clinical Results with Edrecolomab as a Vaccine for Induction of Anti-idiotypic Response 188
10.3.3 EpCAM Protein as a Vaccine in Colorectal Cancer 189
10.3.4 Adecatumumab， a Novel Fully Human Anti-EpCAM Antibody 190
10.4 Therapeutic Window of EpCAM-directed Therapies 192
10.5 Conclusions 196
References 198
11 Carcinoembryonic Antigen 201
11.1 CEA Biology 201
11.1.1 C EA Gene Family， Genomic Localization， Protein Structure 201
11.1.2 Evolution 203
11.1.3 Expression 203
11.1.4 Biological Functions 204
11.2 Clinical Relevance of CEA 206
11.2.1 CEA as a Tumor Marker for Prognosis and Post-surgery Follow-up 206
11.2.2 Targeting CEA for Tumor Localization and Therapy 207
11.2.2.1 Animal Models for CEA 207
11.2.2.2 Tumor Localization and Therapy with Anti-CEA Antibodies 207
11.2.2.3 CEA-based Vaccines 209
11.2.3 Immune Monitoring 211
11.3 Conclusion 213
References 213
12 HER-2 as a Tumor Antigen 219
12.1 Introduction 219
12.2 Biology of HER2 219
12.2.1 Features of HER2 219
12.2.2 The Self-antigen HER2 as a Potential Therapeutic Target 220
12.2.3 Determination of HER2 Status in Tumors 222
12.3 General Approaches for Targeting HER2 using Anti-cancer Agents 222
12.4 Active HER2-based Cancer Vaccines 222
12.4.1 HER2-specific Peptides 223
12.4.2 T Cell-mediated Immunity to HER2 in Cancer Patients 224
12.5 Passive Immunotherapy Targeting HER2 224
12.6 HER2 Effects on ImmunogenicitF. Both Sides of the Coin 225
12.7 Conclusions 226
References 227
13 Epstein-Barr Virus-associated Antigens 231
13.1 Introduction 231
13.2 Functions of EBV Antigens in Latently Infected Cells 232
13.2.1 EBV Nuclear Antigen 1 (EBNA1) 233
13.2.2 EBV Nuclear Antigen 2 and Leader Protein (EBNA2 and EBNA-LP) 233
13.2.3 EBV Nuclear Antigen Family 3 (EBNA3) 234
13.2.4 Latent Membrane Protein 1 (LMP1) 234
13.2.5 Latent Membrane Protein 2 (LMP2) 235
13.3 T-cell Responses to EBV Antigens 236
13.3.1 CD8+ T-cell Responses 236
13.3.2 CD4+ T-cell Response 237
13.4 EBV-associated Malignancies 237
13.4.1 Post-Transplant Lymphoproliferative Disease (PTLD) 237
13.4.2 Adoptive T-cell Therapy 238
13.4.3 Burkitt's Lymphoma and Hodgkin's Lymphoma 240
References 241
14 Human Papillomavirus (HPV) Tumor-associated Antigens 249
14.1 Introduction 249
14.2 HPV-encoded TAA 250
14.2.1 The Proteins of HPV 250
14.2.2 Vaccine Development 253
14.2.3 Therapeutic Vaccine Strategies 253
14.2.4 HPV-induced Cellular TAA 256
14.3 Conclusions and Future Perspectives 256
References 257
15 Circulating TAAs: Biomarkers for Cancer Diagnosis， CA125 261
15.1 Introduction 261
15.2 Definition and Classification of Mucins 261
15.3 Structure of MUC 16 263
15.3.1 Gene and Protein Structure 263
15.3.1.1 Domain I 263
15.3.1.2 Domain II 263
15.3.1.3 Domain III 265
15.3.2 Evolutionary Considerations 266
15.4 Distribution of MUC16 266
15.5 MUC16 Function in Normal Tissues 266
15.6 Release ofMUC16:CA125 Tumor Marker 267
15.6.1 History 267
15.6.2 Assay Methods 268
15.6.3 Serum CA125 Levels in Healthy Subjects 269
15.6.3.1 Age 269
15.6.3.2 Menstrual cycle 270
15.6.3.3 Pregnancy 270
15.6.3.4 Race 270
15.6.3.5 Other Factors that may affect CA125 Levels 270
15.6.4 Serum CA125 Levels in Patients with Benign Diseases 270
15.6.5 Serum CA125 Levels in Non-ovarian Cancer 270
15.6.6 Serum CA125 Levels in Ovarian Cancers 270
15.7 Clinical Applications 271
15.7.1 Screening 271
15.7.2 Evaluating Pelvic Masses 272
15.7.3 Assessing Prognosis 272
15.7.4 Assessing Response to Therapy 273
15.7.5 Follow-up after Completion of Initial Therapy 274
15.8 Novel Markers 274
15.9 Conclusions 276
References 276
Part Four Clinical Applications of TAAs 281
16 Overview of Cancer Vaccines 283
16.1 Introduction 283
16.2 Cellular Immune Responses in Tumor Rejection 283
16.3 Selection of TAAs for the Development of Cancer Vaccines 284
16.4 Types of Cancer Vaccine 285
16.4.1 Defined Antigen Approaches 285
16.4.1.1 Peptides 285
16.4.1.2 Recombinant Protein 286
16.4.1.3 DNA 287
16.4.1.4 Viral Vectors 288
16.4.2 Undefined Antigens 289
16.4.2.1 Autologous Tumor Cell Vaccines 289
16.4.2.2 Allogeneic Tumor Cell Vaccines 290
16.4.2.3 Loading DCs with Tumor Preparations 290
16.5 Immune Biomarkers 292
16.6 Problems with the Assessment of Clinical Trials for Cancer Vaccines 292
16.6.1 Biomarkers 294
16.6.2 Schedule and Protocol 294
16.7 Combined Therapies; Synergy with Conventional Approaches 294
16.8 Conclusion 295
References 296
17 Tumor-associated Antigenic Peptides as Vaccine Candidates 303
17.1 Introduction 303
17.2 Different Types of Antigens 304
17.2.1 Mutation Antigens 304
17.2.2 Shared Tumor-specific Antigens 306
17.2.3 Differentiation Antigens 308
17.2.4 Over-Expressed Antigens 309
17.2.5 Viral Antigens 311
17.3 Conclusions 312
References 313
18 DNA Vaccines for the Human Papilloma Virus 317
18.1 Introduction 317
18.1.1 HPV and Cervical Cancer 317
18.1.2 Events in the Progression from HPV Infection to Cervical Cancer 318
18.1.3 HPV Antigens for Vaccine Development 318
18.2 DNAVaccines for HPV 319
18.2.1 Preventive HPV DNA Vaccines 319
18.2.2 Therapeutic HPV DNA Vaccines 321
18.2.2.1 Importance of DCs in Enhancing DNA Vaccine Potency 322
18.2.2.2 Clinical Progress in HPV DNA Vaccine Development 329
18.2.3 Combined Approaches 331
18.2.3.1 Combined Preventive and Therapeutic HPV DNA Vaccines 331
18.2.3.2 HPV DNA Vaccines in Combination with Other Therapies 331
18.3 Conclusion 332
References 332
19 Adoptive T-cell Transfer in Cancer Treatment 339
19.1 Introduction 339
19.2 T Cell-based Therapies 339
19.2.1 Therapy of Virus-associated Cancers with Antigen-specific T Cells 339
19.2.2 T Cells with Specificity for Self-antigens 342
19.2.3 T Cells with Specificity for Alloantigens 343
19.2.4 Engineered T Cells 344
19.2.5 Safety Concerns and Suicide Gene Transfer 345
19.3 Conclusion 346
References 346
Index 355
