Gene Therapy of Cancer (eBook)

Front Cover 1
Gene Therapy of Cancer 4
Copyright Page 5
Contents 8
Contributors 16
Preface 20
PART I: VECTORS FOR GENE THERAPY OF CANCER 22
Chapter 1. Retroviral Vector Design for Cancer Gene Therapy 24
I. Introduction 24
II. Applications for Retroviral Vectors in Oncology 25
III. Biology of Retroviruses 27
IV. Principles of Retroviral Vector Systems 30
V. Advances in Retroviral Vector Tailoring 32
VI. Outlook 43
References 44
Chapter 2. Noninfectious Gene Transfer and Expression Systems for Cancer Gene Therapy 52
I. Introduction 52
II. Advantages and Disadvantages of Infectious, Viral-Based Vectors for Human Gene Therapy 52
III. Rationale for Considering Noninfectious, Plasmid-Based Expression Systems 54
IV. Gene Transfer Technologies for Plasmid-Based Vectors: Preclinical Models and Clinical Cancer Gene Therapy Trials 54
V. Plasmid Expression Vectors 58
VI. Future Directions 64
References 66
Chapter 3. Parvovirus Vectors for the Gene Therapy of Cancer 74
I. Introduction 74
II. Biology of Parvoviridae and Vector Development 75
III. Applications of Recombinant Parvovirus Vectors to Cancer Gene Therapy 82
IV. Perspectives, Problems, and Future Considerations References 92
References 92
Chapter 4. Antibody-Targeted Gene Therapy 102
I. Introduction 102
II. Background: Monoclonal Antibodies and Cancer Therapy 102
III. Recent Advances: Monoclonal-Antibody-Mediated Targeting and Cancer Gene Therapy 105
IV. Future Directions 112
References 113
Chapter 5. Ribozymes in Cancer Gene Therapy 116
I. Introduction 116
II. Ribozyme Structures and Functions 117
III. Cancer Disease Models for Ribozyme Application 119
IV. Challenges and Future Directions 123
References 124
Chapter 6. The Advent of Lentiviral Vectors: Prospects for Cancer Therapy 130
I. Introduction 130
II. Structure and Function of Lentiviruses 131
III. Features that Distinguish Lentiviral from Oncoretroviral Vectors 132
IV. Manufacture of Lentiviral Vectors 134
V. Possible Applications of Lentiviral Vectors in Cancer Therapy 138
VI. Conclusions 140
References 141
PART II: IMMUNE TARGETED GENE THERAPY 146
Chapter 7. Immunologic Targets for the Gene Therapy of Cancer 148
I. Introduction 149
II. Cellular (T-Lymphocyte-Mediated) Versus Humoral (Antibody-Mediated) Immune Responses to Tumor Cells 149
III. Response of CD4+ and CD8+ T Lymphocytes to Tumor Antigens Presented in the Context of Molecules Encoded by the Major Histocompatibility Complex 150
IV. Response of Tumor-Bearing Individuals to Tumor Antigens 153
V. Tumor-Associated Peptides as Candidate Targets for Tumor-Specific Lymphocytes 154
VI. Immunotherapeutic Strategies for the Treatment of Cancer 156
VII.Conclusions 159
References 159
PART IIa: VACCINE STRATEGIES 164
Chapter 8. Development of Epitope-Specific Immunotherapies for Human Malignancies and Premalignant Lesions Expressing Mutated ras Genes 166
I. Introduction 166
II. Cellular Immune Response and Antigen Recognition 167
III. Pathways of Antigen Processing, Presentation, and Epitope Expression 167
IV. T-Lymphocyte Subsets 168
V. ras Oncogenes in Neoplastic Development 168
VI. Cellular Immune Responses Induced by ras Oncogene Peptides 170
VII. Identification of Mutant ras CD4+ and CD8+ T-Cell Epitopes Reflecting Codon 12 Mutations 170
VIII. Anti-ras Immune System Interactions: Implications for Tumor Immunity and Tumor Escape 177
IX. Paradigm for Anti-ras Immune System Interactions in Cancer Immunotherapy 179
X. Future Directions 180
References 181
PART IIb: DENDRITIC CELL-BASED GENE THERAPY 186
Chapter 9. Introduction to Dendritic Cells 188
I. Introduction 188
II. Features of Dendritic Cells 188
III. Dendritic Cell Subsets 190
IV. Functional Heterogeneity of Dendritic Cell Subsets 192
V. Dendritic Cells in Tumor Immunology 193
VI. Dendritic Cells and Gene Therapy 194
VII. Conclusions 195
References 195
Chapter 10. DNA and Dendritic Cell-Based Genetic Immunization Against Cancer 200
I. Introduction 200
II. Background 200
III. Recent Advances: Methods of Genetic Immunization 204
IV. Preclinical Development and Translation to the Clinic 211
V. Proposed and Current Clinical Trials 211
VI. Future Directions 212
References 212
Chapter 11. RNA-Transfected Dendritic Cells as Immunogens 220
I. Introduction 220
II. Advantages of Loading Dendritic Cells with Genetic Material 220
III. Viral Versus Nonviral Methods of Gene Transfer 221
IV. RNA Versus DNA Loading of Dendritic Cells 221
V. RNA Loading of Dendritic Cells 222
VI Amplification of RNA Used to Load Dendritic Cells 222
VII. Uses of RNA-Loaded Dendritic Cells 222
VIII. Future Directions 223
References 223
PART IIc: CYTOKINES AND CO-FACTORS 226
Chapter 12. In Situ Immune Modulation Using Recombinant Vaccinia Virus Vectors: Preclinical Studies to Clinical Implementation 228
I. Introduction 228
II. Generation of Cell-Mediated Immune Responses 229
III. Cytokine Gene Transfer Studies in Antitumor Immunity 231
IV. In Situ Cytokine Gene Transfer to Enhance Antitumor Immunity 231
V. Future Directions 236
VI. Conclusions 239
References 240
Chapter 13. The Use of Particle-Mediated Gene Transfer for Immunotherapy of Cancer 246
I. Introduction 246
II. Background 246
III. Recent Advances 249
IV. Issues Regarding Evaluation in Clinical Trials 255
V. Recent Clinical Trials 255
VI. Potential Novel Uses and Future Directions 256
References 256
PART IId: GENETICALLY MODIFIED EFFECTOR CELLS FOR IMMUNE-BASED IMMUNOTHERAPY 260
Chapter 14. Applications of Gene Transfer in the Adoptive Immunotherapy of Cancer 262
I. Introduction 262
II. Use of Gene-Modified Tumors to Generate Antitumor- Reactive T Cells 263
III. Genetic Manipulation of T Cells to Enhance Antitumor Reactivity 267
IV. Genetic Modulation of Dendritic Cells 271
V. Summary 272
References 272
Chapter 15. Update on the Use of Genetically Modified Hematopoietic Stem Cells for Cancer Therapy 278
I. Introduction 278
II. Human Hematopoietic Stem Cells as Vehicles of Gene Transfer 279
III. Preclinical Studies of Gene Transfer into Hematopoietic Stem Cells 280
IV. Applications of Genetically Manipulated Hematopoietic Stem Cells to the Therapy of Human Cancer 283
V. Conclusions 289
References 289
PART III: ONCOGENE-TARGETED GENE THERAPY 292
Chapter 16. Clinical Applications of Tumor-Suppressor Gene Therapy 294
I. Introduction 294
II. p53 294
III. BRCA1 296
IV. Onyx-015 Adenoviruses 296
V. Summary and Future Work 297
References 298
Chapter 17. Cancer Gene Therapy with Tumor Suppressor Genes Involved in Cell-Cycle Control 300
I. Introduction 300
II. p21WAF1/CIP1 301
III. p16INK4 305
IV. Rb 306
V. p14ARF 307
VI. p27Kip1 307
VII. E2F-1 308
VIII. PTEN 309
IX. BRCA1 309
X. VHL 310
XI. FHIT 310
XII. Apoptosis-Inducing Genes 310
XIII. Conclusions 312
References 312
Chapter 18. Cancer Gene Therapy with the p53 Tumor Suppressor Gene 320
I. Introduction 320
II. Vectors for Gene Therapy 321
III. p53 323
IV. Conclusions 329
References 329
Chapter 19. Antisense Downregulation of the Apoptosis-Related Bcl-2 and Bcl-xl Proteins: A New Approach to Cancer Therapy 336
I. The Bcl Family of Proteins and their Role in Apoptosis 336
II. Downregulation of Bcl-2 Expression: Antisense Strategies 337
References 345
Chapter 20. Gene Therapy for Chronic Myelogenous Leukemia 352
I. Molecular Mechanisms Underlying Ph+ Leukemias 352
II. Therapy 352
III. Gene-Disruption Methods 353
IV. Anti-bcr-abl Targeted Therapies 353
V. Anti-bcr-abl Drug-Resistance Gene Therapy for CML 353
VI. Conclusion 355
References 355
PART IV: MANIPULATION OF DRUG RESISTANCE MECHANISMS BY GENE THERAPY 360
Chapter 21. Transfer of Drug-Resistance Genes into Hematopoietic Progenitors 362
I. Introduction 362
II. Rationale for Drug-Resistance Gene Therapy 363
III. Methyltransferase-Mediated Drug Resistance 365
IV. Cytidine Deaminase 369
V. Glutathione-S-Transferase 369
VI. Dual-Drug-Resistance Approach 370
VII. Clinical Trials 371
VIII. Conclusion 372
References 372
Chapter 22. Multidrug-Resistance Gene Therapy in Hematopoietic Cell Transplantation 376
I. Introduction 376
II. P-Glycoprotein 377
III. Targeting Hematopoietic Progenitor Cells for Genetic Modification 377
IV. Expression of P-Glycoprotein in Murine Hematopoietic Progenitors 378
V. Expression of P-Glycoprotein in Human Hematopoietic Progenitors 379
VI. Results of Early Phase I Studies Using MDR1-Transduced Hematopoietic Cells 380
VII. Overcoming Transduction Inefficiency 381
VIII. MDR1 Gene Transfer into Humans: Recent Progress 382
IX. Implication and Future of MDR1 Gene Therapy in Humans 382
References 383
Chapter 23. Development and Application of an Engineered Dihydrofolate Reductase and Cytidine-Deaminase-Based Fusion Genes in Myeloprotection-Based Gene Therapy Strategies 386
I. Introduction 386
II. Fusion Genes 389
III. Development of Clinically Applicable Gene Transfer Approaches 391
IV. Preclinical Evidence for Myeloprotection Strategies 392
V. Clinical Applications of Myeloprotection Strategies 394
VI. Challenges 398
References 399
Chapter 24. Protection from Antifolate Toxicity by Expression of Drug-Resistant Dihydrofolate Reductase 404
I. Introduction 404
II. Drug-Resistant Dihydrofolate Reductases 405
III. Protection from Antifolate Toxicity In Vitro 406
IV. Protection from Antifolate Toxicity In Vivo: Retroviral Transduction Studies 407
V. Dihydrofolate Reductase Transgenic Mouse System for In Vivo Drug-Resistance Studies 407
VI. Antitumor Studies in Animals Expressing Drug-Resistant Dihydrofolate Reductase 408
VII. Antifolate-Mediated In Vivo Selection of Hematopoietic Cells Expressing Drug-Resistant Dihydrofolate Reductase 409
VIII. Summary and Future Considerations 409
References 410
Chapter 25. A Genomic Approach to the Treatment of Breast Cancer 414
I. Introduction 414
II. Toward a Genomic Approach to Therapy 414
III. The Use of DNA Microarrays to Understand Drug Resistance 417
IV. Effects of Genomic-Based Approaches on the Management of Breast Cancer Patients 419
References 420
PART V: ANTI-ANIOGENESIS AND PRO-APOPTOTIC GENE THERAPY 424
Chapter 26. Antiangiogenic Gene Therapy 426
I. Introduction 426
II. Angiogenesis and its Role in Tumor Biology 426
III. Antiangiogenic Therapy of Cancer and the Role of Gene Therapy 427
IV. Preclinical Models of Antiangiogenic Gene Therapy 428
V. Inhibiting Proangiogenic Cytokines 433
VI. Endothelial Cell-Specific Gene Delivery 435
VII. Future Directions in Antiangiogenic Gene Therapy 436
References 436
Chapter 27. VEGF-Targeted Antiangiogenic Gene Therapy 442
I. Introduction 442
II. Angiogenesis and Tumor Growth 443
III. Gene Therapy for Delivery of Antiangiogenic Factors 443
IV. Antiangiogenic Gene Therapy in the Experimental and Clinical Settings 444
V. Vascular Endothelial Growth Factor and Receptors 444
VI. Vascular Endothelial Growth Factor and Angiogenesis 445
VII. Vascular Endothelial Growth Factor Inhibition by Gene Transfer 446
VIII. Issues Regarding Clinical Translation of Antiangiogenic Gene Therapy 449
IX. Conclusion 453
References 453
Chapter 28. Strategies for Combining Gene Therapy with Ionizing Radiation to Improve Antitumor Efficacy 456
I. Introduction 456
II. Strategies Using Gene Therapy to Increase the Efficacy of Radiation Therapy 457
III. Enhancing the Replicative Potential of Antitumor Viruses with Ionizing Radiation 461
IV. Transcriptional Targeting of Gene Therapy with Ionizing Radiation (Genetic Radiotherapy) 462
V. Summary and Future Directions 464
References 465
Chapter 29. Virotherapy with Replication-Selective Oncolytic Adenoviruses: A Novel Therapeutic Platform for Cancer 470
I. Introduction 470
II. Attributes of Replication-Selective Adenoviruses for Cancer Treatment 472
III. Biology of Human Adenovirus 472
IV. Mechanisms of Adenovirus-Mediated Cell Killing 472
V. Approaches to Optimizing Tumor-Selective Adenovirus Replication 473
VI. Background: dl1520 (ONYX-015) 473
VII. Clinical Trial Results with Wild-Type Adenovirus: Flawed Study Design 474
VIII. A Novel Staged Approach to Clinical Research with Replication-Selective Viruses: dl1520 (ONYX-015) 475
IX. Results from Clinical Trials with dl1520 (ONYX-015) 476
X. Results from Clinical Trials with dl1520 (ONYX-015): Summary 480
XI. Future Directions 481
XII. Summary 483
References 483
Chapter 30. E1A Cancer Gene Therapy 486
I. Introduction 486
II. HER2 Overexpression and E1A-Mediated Antitumor Activity 486
III. Mechanisms of E1A-Mediated Anti-Tumor Activity 488
IV. E1A Gene Therapy: Preclinical Models 491
V. E1A Gene Therapy: Clinical Trials 493
VI. Conclusion 494
References 494
PART VI: PRODRUG ACTIVATION STRATEGIES FOR GENE THERAPY OF CANCER 500
Chapter 31. Preemptive and Therapeutic Uses of Suicide Genes for Cancer and Leukemia 502
I. Introduction 502
II. Therapeutic Uses of Suicide Genes 503
III. Preemptive Uses of Suicide Genes in Cancer 504
IV. Creation of Stable Suicide Functions by Combining Suicide Gene Transduction with Endogenous Gene Loss 506
V. Preemptive Uses of Suicide Genes to Control Graft-Versus-Host Disease in Leukemia 508
VI. Future Prospects for Preemptive Use of Suicide Genes 509
References 510
Chapter 32. Treatment of Mesothelioma Using Adenoviral-Mediated Delivery of Herpes Simplex Virus Thymidine Kinase Gene in Combination with Ganciclovir 514
I. Introduction 514
II. Clinical Use of HSV-TK in the Treatment of Localized Malignancies 515
III. Challenges and Future Directions 520
References 522
Chapter 33. The Use of Suicide Gene Therapy for the Treatment of Malignancies of the Brain 526
I. Introduction 526
II. Retrovirus Vector for HSV-TK 527
III. Adenovirus Vector for HSV-TK 530
IV. Herpes Simplex Virus Vectors Expressing Endogenous HSV-TK 531
V. Promising Preclinical Studies 531
References 532
Chapter 34. Case Study of Combined Gene and Radiation Therapy as an Approach in the Treatment of Cancer 534
I. Introduction 534
II. Background of the Field 535
III. Recent Advances in Herpes Simplex Virus-Thymidine Kinase Suicide Gene Therapy 536
IV. Combined Herpes Simplex Virus-Thymidine Kinase Suicide Gene Therapy and Radiotherapy 537
V. Issues Regarding Clinical Trials, Translation into Clinical Use, Preclinical Development, Efficacy, Endpoints, and Gene Expression 542
VI. Potential Novel Uses and Future Directions 543
References 544
Index 546