Elsevier S & T

Gene Therapy of Cancer: Translational Approaches from Preclinical Studies to Clinical Implementation

Gerson, Stanton L.; Lattime, Edmund C.; Gerson, Stanton L.

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Table of contents

Cover
Copyright Pageiv
Contentsvii
Contributorsxv
Prefacexix
PART I: VECTORS FOR GENE THERAPY OF CANCER1
Chapter 1. Retroviral Vector Design for Cancer Gene Therapy3
I. Introduction3
II. Applications for Retroviral Vectors in Oncology4
III. Biology of Retroviruses6
IV. Principles of Retroviral Vector Systems9
V. Advances in Retroviral Vector Tailoring11
VI. Outlook22
References23
Chapter 2. Noninfectious Gene Transfer and Expression Systems for Cancer Gene Therapy31
I. Introduction31
II. Advantages and Disadvantages of Infectious, Viral-Based Vectors for Human Gene Therapy31
III. Rationale for Considering Noninfectious, Plasmid-Based Expression Systems33
IV. Gene Transfer Technologies for Plasmid-Based Vectors: Preclinical Models and Clinical Cancer Gen33
V. Plasmid Expression Vectors37
VI. Future Directions43
References45
Chapter 3. Parvovirus Vectors for the Gene Therapy of Cancer53
I. Introduction53
II. Biology of Parvoviridae and Vector Development54
III. Applications of Recombinant Parvovirus Vectors to Cancer Gene Therapy61
IV. Perspectives, Problems, and Future Considerations References71
References71
Chapter 4. Antibody-Targeted Gene Therapy81
I. Introduction81
II. Background: Monoclonal Antibodies and Cancer Therapy81
III. Recent Advances: Monoclonal-Antibody-Mediated Targeting and Cancer Gene Therapy84
IV. Future Directions91
References92
Chapter 5. Ribozymes in Cancer Gene Therapy95
I. Introduction95
II. Ribozyme Structures and Functions96
III. Cancer Disease Models for Ribozyme Application98
IV. Challenges and Future Directions102
References103
Chapter 6. The Advent of Lentiviral Vectors: Prospects for Cancer Therapy109
I. Introduction109
II. Structure and Function of Lentiviruses110
III. Features that Distinguish Lentiviral from Oncoretroviral Vectors111
IV. Manufacture of Lentiviral Vectors113
V. Possible Applications of Lentiviral Vectors in Cancer Therapy117
VI. Conclusions119
References120
PART II: IMMUNE TARGETED GENE THERAPY125
Chapter 7. Immunologic Targets for the Gene Therapy of Cancer127
I. Introduction128
II. Cellular (T-Lymphocyte-Mediated) Versus Humoral (Antibody-Mediated) Immune Responses to Tumor Ce128
III. Response of CD4+ and CD8+ T Lymphocytes to Tumor Antigens Presented in the Context of Molecules129
IV. Response of Tumor-Bearing Individuals to Tumor Antigens132
V. Tumor-Associated Peptides as Candidate Targets for Tumor-Specific Lymphocytes133
VI. Immunotherapeutic Strategies for the Treatment of Cancer135
VII.Conclusions138
References138
PART IIa: VACCINE STRATEGIES143
Chapter 8. Development of Epitope-Specific Immunotherapies for Human Malignancies and Premalignant L145
I. Introduction145
II. Cellular Immune Response and Antigen Recognition146
III. Pathways of Antigen Processing, Presentation, and Epitope Expression146
IV. T-Lymphocyte Subsets147
V. ras Oncogenes in Neoplastic Development147
VI. Cellular Immune Responses Induced by ras Oncogene Peptides149
VII. Identification of Mutant ras CD4+ and CD8+ T-Cell Epitopes Reflecting Codon 12 Mutations149
VIII. Anti-ras Immune System Interactions: Implications for Tumor Immunity and Tumor Escape156
IX. Paradigm for Anti-ras Immune System Interactions in Cancer Immunotherapy158
X. Future Directions159
References160
PART IIb: DENDRITIC CELL-BASED GENE THERAPY165
Chapter 9. Introduction to Dendritic Cells167
I. Introduction167
II. Features of Dendritic Cells167
III. Dendritic Cell Subsets169
IV. Functional Heterogeneity of Dendritic Cell Subsets171
V. Dendritic Cells in Tumor Immunology172
VI. Dendritic Cells and Gene Therapy173
VII. Conclusions174
References174
Chapter 10. DNA and Dendritic Cell-Based Genetic Immunization Against Cancer179
I. Introduction179
II. Background179
III. Recent Advances: Methods of Genetic Immunization183
IV. Preclinical Development and Translation to the Clinic190
V. Proposed and Current Clinical Trials190
VI. Future Directions191
References191
Chapter 11. RNA-Transfected Dendritic Cells as Immunogens199
I. Introduction199
II. Advantages of Loading Dendritic Cells with Genetic Material199
III. Viral Versus Nonviral Methods of Gene Transfer200
IV. RNA Versus DNA Loading of Dendritic Cells200
V. RNA Loading of Dendritic Cells201
VI Amplification of RNA Used to Load Dendritic Cells201
VII. Uses of RNA-Loaded Dendritic Cells201
VIII. Future Directions202
References202
PART IIc: CYTOKINES AND CO-FACTORS205
Chapter 12. In Situ Immune Modulation Using Recombinant Vaccinia Virus Vectors: Preclinical Studies207
I. Introduction207
II. Generation of Cell-Mediated Immune Responses208
III. Cytokine Gene Transfer Studies in Antitumor Immunity210
IV. In Situ Cytokine Gene Transfer to Enhance Antitumor Immunity210
V. Future Directions215
VI. Conclusions218
References219
Chapter 13. The Use of Particle-Mediated Gene Transfer for Immunotherapy of Cancer225
I. Introduction225
II. Background225
III. Recent Advances228
IV. Issues Regarding Evaluation in Clinical Trials234
V. Recent Clinical Trials234
VI. Potential Novel Uses and Future Directions235
References235
PART IId: GENETICALLY MODIFIED EFFECTOR CELLS FOR IMMUNE-BASED IMMUNOTHERAPY239
Chapter 14. Applications of Gene Transfer in the Adoptive Immunotherapy of Cancer241
I. Introduction241
II. Use of Gene-Modified Tumors to Generate Antitumor- Reactive T Cells242
III. Genetic Manipulation of T Cells to Enhance Antitumor Reactivity246
IV. Genetic Modulation of Dendritic Cells250
V. Summary251
References251
Chapter 15. Update on the Use of Genetically Modified Hematopoietic Stem Cells for Cancer Therapy257
I. Introduction257
II. Human Hematopoietic Stem Cells as Vehicles of Gene Transfer258
III. Preclinical Studies of Gene Transfer into Hematopoietic Stem Cells259
IV. Applications of Genetically Manipulated Hematopoietic Stem Cells to the Therapy of Human Cancer262
V. Conclusions268
References268
PART III: ONCOGENE-TARGETED GENE THERAPY271
Chapter 16. Clinical Applications of Tumor-Suppressor Gene Therapy273
I. Introduction273
II. p53273
III. BRCA1275
IV. Onyx-015 Adenoviruses275
V. Summary and Future Work276
References277
Chapter 17. Cancer Gene Therapy with Tumor Suppressor Genes Involved in Cell-Cycle Control279
I. Introduction279
II. p21WAF1/CIP1280
III. p16INK4284
IV. Rb285
V. p14ARF286
VI. p27Kip1286
VII. E2F-1287
VIII. PTEN288
IX. BRCA1288
X. VHL289
XI. FHIT289
XII. Apoptosis-Inducing Genes289
XIII. Conclusions291
References291
Chapter 18. Cancer Gene Therapy with the p53 Tumor Suppressor Gene299
I. Introduction299
II. Vectors for Gene Therapy300
III. p53302
IV. Conclusions308
References308
Chapter 19. Antisense Downregulation of the Apoptosis-Related Bcl-2 and Bcl-xl Proteins: A New Appro315
I. The Bcl Family of Proteins and their Role in Apoptosis315
II. Downregulation of Bcl-2 Expression: Antisense Strategies316
References324
Chapter 20. Gene Therapy for Chronic Myelogenous Leukemia331
I. Molecular Mechanisms Underlying Ph+ Leukemias331
II. Therapy331
III. Gene-Disruption Methods332
IV. Anti-bcr-abl Targeted Therapies332
V. Anti-bcr-abl Drug-Resistance Gene Therapy for CML332
VI. Conclusion334
References334
PART IV: MANIPULATION OF DRUG RESISTANCE MECHANISMS BY GENE THERAPY339
Chapter 21. Transfer of Drug-Resistance Genes into Hematopoietic Progenitors341
I. Introduction341
II. Rationale for Drug-Resistance Gene Therapy342
III. Methyltransferase-Mediated Drug Resistance344
IV. Cytidine Deaminase348
V. Glutathione-S-Transferase348
VI. Dual-Drug-Resistance Approach349
VII. Clinical Trials350
VIII. Conclusion351
References351
Chapter 22. Multidrug-Resistance Gene Therapy in Hematopoietic Cell Transplantation355
I. Introduction355
II. P-Glycoprotein356
III. Targeting Hematopoietic Progenitor Cells for Genetic Modification356
IV. Expression of P-Glycoprotein in Murine Hematopoietic Progenitors357
V. Expression of P-Glycoprotein in Human Hematopoietic Progenitors358
VI. Results of Early Phase I Studies Using MDR1-Transduced Hematopoietic Cells359
VII. Overcoming Transduction Inefficiency360
VIII. MDR1 Gene Transfer into Humans: Recent Progress361
IX. Implication and Future of MDR1 Gene Therapy in Humans361
References362
Chapter 23. Development and Application of an Engineered Dihydrofolate Reductase and Cytidine-Deamin365
I. Introduction365
II. Fusion Genes368
III. Development of Clinically Applicable Gene Transfer Approaches370
IV. Preclinical Evidence for Myeloprotection Strategies371
V. Clinical Applications of Myeloprotection Strategies373
VI. Challenges377
References378
Chapter 24. Protection from Antifolate Toxicity by Expression of Drug-Resistant Dihydrofolate Reduct383
I. Introduction383
II. Drug-Resistant Dihydrofolate Reductases384
III. Protection from Antifolate Toxicity In Vitro385
IV. Protection from Antifolate Toxicity In Vivo: Retroviral Transduction Studies386
V. Dihydrofolate Reductase Transgenic Mouse System for In Vivo Drug-Resistance Studies386
VI. Antitumor Studies in Animals Expressing Drug-Resistant Dihydrofolate Reductase387
VII. Antifolate-Mediated In Vivo Selection of Hematopoietic Cells Expressing Drug-Resistant Dihydrof388
VIII. Summary and Future Considerations388
References389
Chapter 25. A Genomic Approach to the Treatment of Breast Cancer393
I. Introduction393
II. Toward a Genomic Approach to Therapy393
III. The Use of DNA Microarrays to Understand Drug Resistance396
IV. Effects of Genomic-Based Approaches on the Management of Breast Cancer Patients398
References399
PART V: ANTI-ANIOGENESIS AND PRO-APOPTOTIC GENE THERAPY403
Chapter 26. Antiangiogenic Gene Therapy405
I. Introduction405
II. Angiogenesis and its Role in Tumor Biology405
III. Antiangiogenic Therapy of Cancer and the Role of Gene Therapy406
IV. Preclinical Models of Antiangiogenic Gene Therapy407
V. Inhibiting Proangiogenic Cytokines412
VI. Endothelial Cell-Specific Gene Delivery414
VII. Future Directions in Antiangiogenic Gene Therapy415
References415
Chapter 27. VEGF-Targeted Antiangiogenic Gene Therapy421
I. Introduction421
II. Angiogenesis and Tumor Growth422
III. Gene Therapy for Delivery of Antiangiogenic Factors422
IV. Antiangiogenic Gene Therapy in the Experimental and Clinical Settings423
V. Vascular Endothelial Growth Factor and Receptors423
VI. Vascular Endothelial Growth Factor and Angiogenesis424
VII. Vascular Endothelial Growth Factor Inhibition by Gene Transfer425
VIII. Issues Regarding Clinical Translation of Antiangiogenic Gene Therapy428
IX. Conclusion432
References432
Chapter 28. Strategies for Combining Gene Therapy with Ionizing Radiation to Improve Antitumor Effic435
I. Introduction435
II. Strategies Using Gene Therapy to Increase the Efficacy of Radiation Therapy436
III. Enhancing the Replicative Potential of Antitumor Viruses with Ionizing Radiation440
IV. Transcriptional Targeting of Gene Therapy with Ionizing Radiation (Genetic Radiotherapy)441
V. Summary and Future Directions443
References444
Chapter 29. Virotherapy with Replication-Selective Oncolytic Adenoviruses: A Novel Therapeutic Platf449
I. Introduction449
II. Attributes of Replication-Selective Adenoviruses for Cancer Treatment451
III. Biology of Human Adenovirus451
IV. Mechanisms of Adenovirus-Mediated Cell Killing451
V. Approaches to Optimizing Tumor-Selective Adenovirus Replication452
VI. Background: dl1520 (ONYX-015)452
VII. Clinical Trial Results with Wild-Type Adenovirus: Flawed Study Design453
VIII. A Novel Staged Approach to Clinical Research with Replication-Selective Viruses: dl1520 (ONYX-454
IX. Results from Clinical Trials with dl1520 (ONYX-015)455
X. Results from Clinical Trials with dl1520 (ONYX-015): Summary459
XI. Future Directions460
XII. Summary462
References462
Chapter 30. E1A Cancer Gene Therapy465
I. Introduction465
II. HER2 Overexpression and E1A-Mediated Antitumor Activity465
III. Mechanisms of E1A-Mediated Anti-Tumor Activity467
IV. E1A Gene Therapy: Preclinical Models470
V. E1A Gene Therapy: Clinical Trials472
VI. Conclusion473
References473
PART VI: PRODRUG ACTIVATION STRATEGIES FOR GENE THERAPY OF CANCER479
Chapter 31. Preemptive and Therapeutic Uses of Suicide Genes for Cancer and Leukemia481
I. Introduction481
II. Therapeutic Uses of Suicide Genes482
III. Preemptive Uses of Suicide Genes in Cancer483
IV. Creation of Stable Suicide Functions by Combining Suicide Gene Transduction with Endogenous Gene485
V. Preemptive Uses of Suicide Genes to Control Graft-Versus-Host Disease in Leukemia487
VI. Future Prospects for Preemptive Use of Suicide Genes488
References489
Chapter 32. Treatment of Mesothelioma Using Adenoviral-Mediated Delivery of Herpes Simplex Virus Thy493
I. Introduction493
II. Clinical Use of HSV-TK in the Treatment of Localized Malignancies494
III. Challenges and Future Directions499
References501
Chapter 33. The Use of Suicide Gene Therapy for the Treatment of Malignancies of the Brain505
I. Introduction505
II. Retrovirus Vector for HSV-TK506
III. Adenovirus Vector for HSV-TK509
IV. Herpes Simplex Virus Vectors Expressing Endogenous HSV-TK510
V. Promising Preclinical Studies510
References511
Chapter 34. Case Study of Combined Gene and Radiation Therapy as an Approach in the Treatment of Can513
I. Introduction513
II. Background of the Field514
III. Recent Advances in Herpes Simplex Virus-Thymidine Kinase Suicide Gene Therapy515
IV. Combined Herpes Simplex Virus-Thymidine Kinase Suicide Gene Therapy and Radiotherapy516
V. Issues Regarding Clinical Trials, Translation into Clinical Use, Preclinical Development, Efficac521
VI. Potential Novel Uses and Future Directions522
References523
Index525

Book details

Vendor Elsevier S & T
SKU 9780124375512
ISBN-13 9780080491363
Author Gerson, Stanton L.; Lattime, Edmund C.; Gerson, Stanton L.
Edition 2nd
Category Medical
Subject Oncology

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The Second Edition of Gene Therapy of Cancer provides crucial updates on the basic science and ongoing research in this field, examining the state of the art technology in gene therapy and its therapeutic applications to the treatment of cancer. The clinical chapters are improved to include new areas of research and more successful trials. Chapters emphasize the scientific basis of gene therapy using immune, oncogene, antisense, pro-drug activating, and drug resistance gene targets, while other chapters discuss therapeutic approaches and clinical applications. This book is a valuable reference for anyone needing to stay abreast of the latest advances in gene therapy treatment for cancer.

Key Features
* Provides in-depth description of targeted systems and treatment strategies
* Explains the underlying cancer biology necessary for understanding a given therapeutic approach
* Extensively covers immune therapeutics of vaccines, cytokines, and peptide-induced responses
* Presents translational focus with emphasis on requirements for clinical implementation
* Incorporates detailed illustrations of vectors and therapeutic approaches ideal for classroom presentations and general reference

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