Gene-Based Therapies for Cancer (eBook)

Foreword 6
Contents 8
Contributors 10
Chapter 1: RNAi: A New Paradigm in Cancer Gene Therapy 16
1 Introduction 17
2 Clinical Significance of the RNAi Processing Machinery 18
3 Clinical Application of RNAi 19
4 Off-Target Effects 23
5 RNAi Imaging: Biodistribution and Target Modulation 25
6 Development of RNAi-Based Gene Therapy: Clinical Trials 26
7 Future Development 27
References 28
Chapter 2: Gene-Based Therapy for Cancer: Brain Tumors 31
1 Introduction 31
2 Replication-Deficient Viral Vectors 32
2.1 Ad-p53 32
2.2 HSVtk/GCV Gene Therapy 34
3 Oncolytic Viruses 35
3.1 Adenovirus 35
3.1.1 ONYX-015 36
3.1.2 Delta-24-RGD 37
3.2 Herpes Simplex Virus-1 38
3.3 Reovirus 39
3.4 Measles Virus 40
3.5 Newcastle Disease Virus 40
4 Future Perspectives 41
References 42
Chapter 3: Gene Therapy of Prostate Cancer 47
1 Introduction 47
2 Enzyme/Prodrug Gene Therapy 48
2.1 Enzyme/Prodrug Gene Therapy Using Replication-Defective Adenoviruses 48
2.2 Enzyme/Prodrug Gene Therapy Using Replication-Competent Adenoviruses 50
3 Vaccine-Based Gene Therapy Strategies 55
3.1 Poxvirus-Based Vaccines 55
3.2 Cell-Based Vaccines 57
4 Replication-Competent, Oncolytic Adenoviruses 58
5 Summary 59
References 60
Chapter 4: siRNA Versus shRNA for Personalized Cancer Therapy: Mechanisms and Applications 64
1 Introduction 65
2 Personalized Cancer Therapy 65
3 Mechanisms of RNAi 66
3.1 siRNA 66
3.2 shRNA 68
3.2.1 Bifunctional shRNA 69
4 SiRNA Versus shRNA 70
4.1 Comparative Efficacy 70
4.2 Dicer/Drosha Expression in Cancer and RNAi Effector Suitability 70
4.3 Off-Target Effects 71
4.3.1 Specific Off-Target Effects 71
4.3.2 Nonspecific Off-Target Effects 71
5 Delivery Strategies for Clinical Translation 72
6 Conclusions 73
References 73
Chapter 5: Tumor Suppressor Gene Therapy 76
1 Tumor Suppressor Gene Therapy 77
2 Gene Replacement by p53 in Laboratory Studies 78
3 Clinical Trials of p53 Gene Replacement 79
4 Gene Replacement in Combination with DNA Damaging Agents 81
5 Clinical Trials of Tumor Suppressor Gene Replacement Combined with Chemotherapy 82
6 Clinical Trials of p53 Gene Replacement Combined with Radiation Therapy 82
7 Systemic Gene Therapy for Metastases 84
8 Summary and Conclusions 87
References 88
Chapter 6: Targeted Oncolytic Adenovirus for Human Cancer Therapy: Gene-Based Therapies for Cancer 92
1 Introduction 92
2 Telomerase Activity for Transcriptional Cancer Targeting 94
3 Telomerase-Specific Oncolytic Adenovirus for Cancer Therapeutics 94
3.1 Structure of hTERT Promoter-Driven Oncolytic Adenovirus 94
3.2 Preclinical Studies of hTERT Promoter-Driven Oncolytic Adenovirus 95
3.3 Immune Activation by hTERT Promoter-Driven Oncolytic Adenovirus 98
4 Telomerase-Specific Oncolytic Adenovirus for Cancer Diagnostics 99
4.1 hTERT Promoter-Driven GFP-Expressing Oncolytic Adenovirus 99
4.2 Ex vivo Imaging of Human Circulating Tumor Cells with GFP Fluorescence 99
4.3 In Vivo Imaging of Lymph Node Micrometastasis with GFP Fluorescence 100
5 Clinical Application of Telomerase-Specific Oncolytic Adenovirus 101
6 Conclusions and Perspectives 101
References 103
Chapter 7: Gene Therapy for Malignant Pleural Mesothelioma 107
1 Background 107
2 MPM as a Target for Gene Therapy 108
3 Preclinical Investigations 108
3.1 Induction of Apoptosis 108
3.2 Antiangiogenesis 110
3.3 Suicide-Gene Therapy 110
3.4 Immunogene Therapy 112
3.5 Replicating, Tumor-Selective Oncolytic Viral Vectors 113
4 Clinical Investigations 114
4.1 Suicide Gene Therapy 114
4.2 Cytokine Gene Therapy 116
5 Summary 118
References 119
Chapter 8: Mesenchymal Stem/Stromal Cells as Cellular Vehicles for Tumor Targeting 124
1 Introduction 124
1.1 Tumor Cell-Centric View on Tumor Development 124
1.2 Stroma is a Common Ground for Numerous Cancers 125
1.3 Role of Fibroblasts and Stromal Precursors 128
2 Tropism of MSC for Wounds and Tumors 129
2.1 But Which Cell in the Stroma to Target 130
2.2 Rationale for Targeting Tumors Using Stromal Precusor Cells 131
2.3 Migratory Factors 132
3 Use of Stem Cells as Cellular Vehicles to Target Tumors 133
3.1 MSC as Cell Vehicles for Cancer 135
4 Interferons 136
5 Interleukins 137
6 Conditionally Replication Adenoviral Vectors 138
7 Chemokines and Growth Factor Antagonists 139
8 Suicide Genes 139
9 Tumor Necrosis Factor-Related Apoptosis Inducing Ligand 140
10 Alternative Mesenchymal Tissues as Sources for Anticancer Therapies 140
11 Conclusions 141
References 142
Chapter 9: Retargeting Adenovirus for Cancer Gene Therapy 151
1 Introduction 151
2 Adenovirus Life Cycle and Genomic Organization 152
3 Strategies for Ad-Based Cancer Gene Therapy 153
3.1 Cancer Gene Therapy Vectors 153
3.2 Immunotherapy Vectors 153
3.3 Virotherapy Vectors 154
4 A Need for Retargeted Adenovirus-Based Vectors for Cancer Therapy 154
5 Transductional Targeting 155
5.1 Adapter-Based Targeting 155
5.2 Genetic Modifications 156
6 Cellular Control of Ad Vector Gene Expression 156
6.1 Transcriptional Targeting 157
6.2 Translational Targeting 158
6.3 Functional Complementation 158
7 Adjunct Technologies for Delivery 159
8 Future Directions and Conclusions 159
References 161
Chapter 10: Lentiviruses: Vectors for Cancer Gene Therapy 164
1 Introduction 164
2 Lentiviruses 166
2.1 Lentiviral Genome and Structure 166
2.2 Lentiviral Life Cycle 167
3 HIV-1 Derived Lentiviral Vector 168
3.1 Lentiviral Vector Packaging System 169
3.2 Design and Improvement of Lentiviral Transfer Vector 169
3.3 Non-HIV-1 Derived Lentiviral Vectors 172
3.4 Pseudotyping Lentiviral Vector 173
3.5 Production of Lentiviral Vector 173
4 Applications of Lentiviral Vector in Cancer Therapy 175
4.1 Suicide Gene Therapy 175
4.2 Lentiviral Immunotherapy for Cancer 175
4.3 Gene Replacement and Gene Silencing 177
4.4 Antiangiogenesis Therapy 177
4.5 Myeloprotection Against Chemotherapeutics 178
5 Clinical Trials of Lentiviral Vectors 178
6 Conclusion 179
References 181
Chapter 11: Interleukin-24 Gene Therapy for Melanoma 189
1 Biology of IL-24 a Tumor Suppressor/Cytokine 189
1.1 Tumor Suppressor Properties 189
1.2 Cytokine Properties 192
2 Expression of IL-24 in Melanocytes and Melanoma 193
3 Re-expression of the Tumor Suppressor 194
4 Clinical Experience with Ad mda-7/IL-24 196
4.1 Metastatic Melanoma 196
4.2 Phase I/II intratumoral Ad-mda-7/IL-24 Gene Transfer in Patients with Advanced Solid Tumors 197
4.3 Phase II Intratumoral Injection of Ad-mda-7/IL-24 in Patients with Advanced Melanoma 198
4.3.1 Clinical Results 199
4.3.2 Laboratory Results 199
Induction of Pro-apoptotic and Anti-proliferative Effects in the Ad-mda-7/IL-24 Injected Melanoma in Transit Lesions 199
Effects of Ad-mda-7/IL-24 on the Peripheral Immune System 200
5 Other Preclinical Studies Using Viral Delivery of IL-24 201
6 Systemic Delivery of Non-viral Nanoparticle-Based Gene Delivery Systems 202
6.1 Preclinical Studies Using DOTAP:chol mda7/IL-24 202
6.2 Current Status of Non-viral Nanoparticles-Based Cancer Gene Therapy Clinical Trials 203
7 Conclusion 204
References 205
Chapter 12: Herpes Simplex Virus 1 for Cancer Therapy 211
1 Herpes Simplex Virus 1 for Cancer Therapy 211
2 Herpes Simplex Virus 1 212
3 Thymidine Kinase (UL23/ICP36) 213
4 ICP 34.5 (RL1) 214
5 Ribonucleotide Reductase (ICP 6) 216
6 ICP 47 216
7 HSV1 Viruses in Clinical Trials for Cancer 217
7.1 G207 217
7.2 HSV1716 219
7.3 NV1020 (RV7020) 225
7.4 HF10 226
7.5 OncoVex GM-CSF 228
8 The Future of Oncolytic HSV1 Cancer Therapy 229
9 Conclusion 231
References 231
Chapter 13: Telomerase as a Target for Cancer Therapeutics 239
1 Telomeres 239
2 Telomerase 241
3 Telomerase and Early Cancer Detection 242
4 Antitelomerase Cancer Therapy 243
5 Telomerase Immunotherapy 244
6 GRN163L (Imetelstat), Oligonucleotide Enzyme Inhibitor 247
7 Telomerase-Associated Gene Therapy 250
8 Ad-hTR-NTR: A Telomerase Targeted Adenoviral Suicide Gene Therapy Vector 250
9 Telomerase Specific Oncolytic Virus 250
10 Concluding Remarks 251
References 252
Chapter 14: Gene Therapy for Sarcoma 258
1 Introduction 258
2 Cytogenetics of Soft Tissue Sarcoma 259
3 Expression Signatures 263
4 Gene Therapy 266
5 Nonviral Vectors 266
6 Viral Vectors 267
7 Summary 269
References 270
Index 276