Tumor-Associated Antigens: Identification, Characterization, and Clinical Applications

Tumor-Associated Antigens: Identification, Characterization, and Clinical Applications......Page 2
Contents......Page 8
List of Contributors......Page 18
Part One: Tumor-associated Antigens (TAAs): Subclasses of TAAs......Page 26
1.1 Introduction......Page 28
1.2 Generation of T-cell Epitopes......Page 29
1.2.1 Subclasses of Tumor-associated T-cell Antigens......Page 30
1.2.1.2 Cancer Testis Antigens......Page 31
1.2.1.4 Overexpressed Antigens......Page 32
1.3 Identification of T-cell Antigens and their Epitopes......Page 33
1.3.1 T-cell Antigens for Cancer Immunotherapy – How are Candidates Selected?......Page 35
References......Page 37
2.1 Introduction......Page 48
2.2.1 Oncofetal Antigens......Page 49
2.2.2 Oncogenes as Tumor Antigens......Page 50
2.2.4 Cancer-Testis (CT) Antigens......Page 51
2.2.5 Minor Histocompatibility Antigens (mHAgs) as Tumor Antigens......Page 52
2.2.6 Human Melanoma Antigens......Page 53
2.2.7 Human Glioma Antigens and Immunosurveillance in the CNS......Page 54
2.2.8 Heat Shock Proteins, Efficient Carriers of Tumor Antigens......Page 55
2.2.9 Dendritic Cells, Efficient Cross-presenters of Tumor Antigens......Page 56
2.2.10 Spontaneous and Vaccine-induced Immunity and the Tumor Microenvironment......Page 58
References......Page 59
Part Two: Methods to Detect TAAs......Page 70
3.1 Introduction......Page 72
3.2 The SEREX Approach......Page 73
3.2.1 Identification of Human Tumor Antigens by SEREX......Page 74
3.2.2.1 Shared Tumor Antigens......Page 75
3.2.2.3 Antigens Encoded by Mutated Genes......Page 76
3.2.2.9 Non-cancer-related Autoantigens......Page 77
3.2.4 Reverse T Cell Immunology......Page 78
3.2.6 The Human Cancer Immunome......Page 79
3.2.7 Perspectives for Vaccine Development......Page 81
3.3 Conclusions......Page 82
References......Page 83
4.1 Introduction......Page 88
4.1.1 A Humoral Response against Self-antigens: The Notion of Tumor-associated Antigens......Page 89
4.2 Implementation of Serum Antibodies: Serological Screening Technologies......Page 90
4.2.1 PROTEOMEX, alias SERPA and SPEARS......Page 91
4.2.1.2 Candidate Biomarkers Identified by PROTEOMEX......Page 92
4.2.2 AMIDA......Page 93
4.2.2.2 Allo-AMIDA......Page 94
4.3.1 Diagnostic TAAs Detected with AMIDA Screening......Page 96
4.4 Conclusions......Page 97
References......Page 98
5.1 Introduction......Page 104
5.2 Technical Aspects......Page 105
5.2.1 Handling of Samples and the Need for Consistent Messenger RNA Amplification......Page 106
5.2.1.1 Collection of Source Material and RNA Isolation......Page 107
5.2.1.2 Single Strand cDNA Synthesis......Page 108
5.2.1.3 Double-stranded cDNA (ds-cDNA) Synthesis......Page 109
5.2.2.1 Linear Amplification......Page 110
5.2.2.2 PCR-based Exponential Amplification......Page 111
5.2.2.3 Target Labeling for cDNA Microarray using Amplified RNA......Page 113
5.2.2.4 Bioinformatics Tools......Page 114
5.2.2.6 Usefulness of Transcriptional Profiling for Antigen Discovery and the Understanding of Tumor–Host Interactions......Page 115
References......Page 118
6.1 Introduction......Page 128
6.2.1 The Procedural Method......Page 129
6.2.2.2 Body Fluids......Page 131
6.2.2.3 SELDI-MS TAAs and Clinical Potential......Page 132
References......Page 133
Part Three: TAAs and Their Usefulness......Page 138
7.1.2 Cure Rates, Treatment Failure and Toxicity......Page 140
7.2.1 Potential Clinical Impact of Childhood TAA and Strategies for their Identification......Page 141
7.2.2 TAA in Childhood Leukemia......Page 142
7.2.3 TAA in Childhood Brain Tumors......Page 144
7.2.4 TAA in Childhood Lymphoma......Page 146
7.2.5 TAA in Pediatric Neuroblastoma......Page 147
7.2.6 TAA in Rhabdomyosarcoma and other Soft Tissue Sarcomas......Page 149
7.2.7 TAA in Osteosarcoma......Page 150
7.2.8 TAA in Tumors of the Ewing Family......Page 151
7.2.9 TAA in Wilms' Tumor......Page 152
7.3 Conclusion......Page 153
References......Page 154
8.1 Introduction......Page 168
8.2.1 DNA Methylation......Page 169
8.2.2 Histone Post-translational Modifications......Page 170
8.3.2.1 HMW-MAA......Page 171
8.3.2.2 Mucins......Page 172
8.3.2.3 CTA......Page 173
References......Page 178
9.1 Introduction......Page 186
9.2 Definitions and Classification......Page 187
9.3.2 Tumors......Page 188
9.4 Function......Page 189
9.5 Immunology......Page 191
9.6 Clinical Trials......Page 192
9.7 Conclusions......Page 197
References......Page 198
10.1 Introduction......Page 204
10.2.1 Frequent and High Level Expression of EpCAM in Primary Tumors of Colon Cancer......Page 206
10.2.2 EpCAM Expression on Colon Cancer Metastases......Page 208
10.2.4 EpCAM Expression on Colon Cancer Stem Cells......Page 209
10.3.1 Clinical Results with Anti-EpCAM Murine Antibody Edrecolomab in Stage II and III CRC......Page 210
10.3.2 Clinical Results with Edrecolomab as a Vaccine for Induction of Anti-idiotypic Response......Page 213
10.3.3 EpCAM Protein as a Vaccine in Colorectal Cancer......Page 214
10.3.4 Adecatumumab, a Novel Fully Human Anti-EpCAM Antibody......Page 215
10.4 Therapeutic Window of EpCAM-directed Therapies......Page 217
10.5 Conclusions......Page 221
References......Page 223
11.1.1 CEA Gene Family, Genomic Localization, Protein Structure......Page 226
11.1.3 Expression......Page 228
11.1.4 Biological Functions......Page 229
11.2.1 CEA as a Tumor Marker for Prognosis and Post-surgery Follow-up......Page 231
11.2.2.2 Tumor Localization and Therapy with Anti-CEA Antibodies......Page 232
11.2.2.3 CEA-based Vaccines......Page 234
11.2.3 Immune Monitoring......Page 236
References......Page 238
12.2.1 Features of HER2......Page 244
12.2.2 The Self-antigen HER2 as a Potential Therapeutic Target......Page 245
12.4 Active HER2-based Cancer Vaccines......Page 247
12.4.1 HER2-specific Peptides......Page 248
12.5 Passive Immunotherapy Targeting HER2......Page 249
12.6 HER2 Effects on Immunogenicity: Both Sides of the Coin......Page 250
12.7 Conclusions......Page 251
References......Page 252
13.1 Introduction......Page 256
13.2 Functions of EBV Antigens in Latently Infected Cells......Page 257
13.2.2 EBV Nuclear Antigen 2 and Leader Protein (EBNA2 and EBNA-LP)......Page 258
13.2.4 Latent Membrane Protein 1 (LMP1)......Page 259
13.2.5 Latent Membrane Protein 2 (LMP2)......Page 260
13.3.1 CD8+ T-cell Responses......Page 261
13.4.1 Post-Transplant Lymphoproliferative Disease (PTLD)......Page 262
13.4.2 Adoptive T-cell Therapy......Page 263
13.4.3 Burkitt's Lymphoma and Hodgkin's Lymphoma......Page 265
References......Page 266
14.1 Introduction......Page 274
14.2.1 The Proteins of HPV......Page 275
14.2.3 Therapeutic Vaccine Strategies......Page 278
14.3 Conclusions and Future Perspectives......Page 281
References......Page 282
15.2 Definition and Classification of Mucins......Page 286
15.3.1.2 Domain II......Page 288
15.3.1.3 Domain III......Page 290
15.5 MUC16 Function in Normal Tissues......Page 291
15.6.1 History......Page 292
15.6.2 Assay Methods......Page 293
15.6.3.1 Age......Page 294
15.6.6 Serum CA125 Levels in Ovarian Cancers......Page 295
15.7.1 Screening......Page 296
15.7.3 Assessing Prognosis......Page 297
15.7.4 Assessing Response to Therapy......Page 298
15.8 Novel Markers......Page 299
References......Page 301
Part Four: Clinical Applications of TAAs......Page 306
16.2 Cellular Immune Responses in Tumor Rejection......Page 308
16.3 Selection of TAAs for the Development of Cancer Vaccines......Page 309
16.4.1.1 Peptides......Page 310
16.4.1.2 Recombinant Protein......Page 311
16.4.1.3 DNA......Page 312
16.4.1.4 Viral Vectors......Page 313
16.4.2.1 Autologous Tumor Cell Vaccines......Page 314
16.4.2.3 Loading DCs with Tumor Preparations......Page 315
16.6 Problems with the Assessment of Clinical Trials for Cancer Vaccines......Page 317
16.7 Combined Therapies; Synergy with Conventional Approaches......Page 319
16.8 Conclusion......Page 320
References......Page 321
17.1 Introduction......Page 328
17.2.1 Mutation Antigens......Page 329
17.2.2 Shared Tumor-specific Antigens......Page 331
17.2.3 Differentiation Antigens......Page 333
17.2.4 Over-Expressed Antigens......Page 334
17.2.5 Viral Antigens......Page 336
17.3 Conclusions......Page 337
References......Page 338
18.1.1 HPV and Cervical Cancer......Page 342
18.1.3 HPV Antigens for Vaccine Development......Page 343
18.2.1 Preventive HPV DNA Vaccines......Page 344
18.2.2 Therapeutic HPV DNA Vaccines......Page 346
18.2.2.1 Importance of DCs in Enhancing DNA Vaccine Potency......Page 347
18.2.2.2 Clinical Progress in HPV DNA Vaccine Development......Page 354
18.2.3.2 HPV DNA Vaccines in Combination with Other Therapies......Page 356
References......Page 357
19.2.1 Therapy of Virus-associated Cancers with Antigen-specific T Cells......Page 364
19.2.2 T Cells with Specificity for Self-antigens......Page 367
19.2.3 T Cells with Specificity for Alloantigens......Page 368
19.2.4 Engineered T Cells......Page 369
19.2.5 Safety Concerns and Suicide Gene Transfer......Page 370
References......Page 371
Index......Page 380