Gene Therapy of Cancer

Gene Therapy of Cancer

Translational Approaches from Preclinical Studies to Clinical Implementation

2nd Edition - February 26, 2002

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  • Editors: Edmund Lattime, Stanton Gerson, Edmund Lattime, Stanton Gerson
  • eBook ISBN: 9780080491363

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Description

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.

Readership

Oncologists, molecular geneticists, and hematologists

Table of Contents

  • Part I Vectors for Gene Therapy of Cancer

    1. Retroviral Vector Design for Cancer Gene Therapy

    I. Introduction

    II. Applications for Retroviral Vectors in Oncology

    III. Biology of Retroviruses

    IV. Principles of Retroviral Vector Systems

    V. Advances in Retroviral Vector Tailoring

    VI. Outlook

    References

    2. Noninfectious Gene Transfer and Expression Systems for Cancer Gene Therapy

    I. Introduction

    II. Advantages and Disadvantages of Infectious, Viral-Based Vectors for Human Gene Therapy

    III. Rationale for Considering Noninfectious, Plasmid-Based Expression Systems

    IV. Gene Transfer Technologies for Plasmid-Based Vectors: Preclinical Models and Clinical Cancer Gene Therapy Trials

    V. Plasmid Expression Vectors

    VI. Future Directions

    References

    3. Parvovirus Vectors for the Gene Therapy of Cancer

    I. Introduction

    II. Biology of Parvoviridae and Vector Development

    III. Applications of Recombinant Parvovirus Vectors to Cancer Gene Therapy

    IV. Perspectives, Problems, and Future Considerations

    References

    4. Antibody-Targeted Gene Therapy

    I. Introduction

    II. Background: Monoclonal Antibodies and Cancer Therapy

    III. Recent Advances: Monoclonal-Antibody-Mediated Targeting and Cancer Gene Therapy

    IV. Future Directions

    References

    5. Ribozymes in Cancer Gene Therapy

    I. Introduction

    II. Ribozyme Structures and Functions

    III. Cancer Disease Models for Ribozyme Application

    IV. Challenges and Future Directions

    References

    6. The Advent of Lentiviral Vectors: Prospects for Cancer Therapy

    I. Introduction

    II. Structure and Function of Lentiviruses

    III. Features that Distinguish Lentiviral from Oncoretroviral Vectors

    IV. Manufacture of Lentiviral Vectors

    V. Possible Applications of Lentiviral Vectors in Cancer Therapy

    VI. Conclusions

    References

    Part II Immune Targeted Gene Therapy

    7. Immunologic Targets for the Gene Therapy of Cancer

    I. Introduction

    II. Cellular (T-Lymphocyte-Mediated) Versus Humoral (Antibody-Mediated) Immune Responses to Tumor Cells

    III. Response of CD4+ and CD8+ T Lymphocytes to Tumor Antigens Presented in the Context of Molecules Encoded by the Major Histocompatibility Complex

    IV. Response of Tumor-Bearing Individuals to Tumor Antigens

    V. Tumor-Associated Peptides as Candidate Targets for Tumor-Specific Lymphocytes

    VI. Immunotherapeutic Strategies for the Treatment of Cancer

    VII.Conclusions

    References

    Part IIa Vaccine Strategies

    8. Development of Epitope-Specific Immunotherapies for Human Malignancies and Premalignant Lesions Expressing Mutated ras Genes

    I. Introduction

    II. Cellular Immune Response and Antigen Recognition

    III. Pathways of Antigen Processing, Presentation, and Epitope Expression

    IV. T-Lymphocyte Subsets

    V. ras Oncogenes in Neoplastic Development

    VI. Cellular Immune Responses Induced by ras Oncogene Peptides

    VII. Identification of Mutant ras CD4+ and CD8+ T-Cell Epitopes Reflecting Codon 12 Mutations

    VIII. Anti-ras Immune System Interactions: Implications for Tumor Immunity and Tumor Escape

    IX. Paradigm for Anti-ras Immune System Interactions in Cancer Immunotherapy

    X. Future Directions

    References

    Part IIb Dendritic Cell-Based Gene Therapy

    9. Introduction to Dendritic Cells

    I. Introduction

    II. Features of Dendritic Cells

    III. Dendritic Cell Subsets

    IV. Functional Heterogeneity of Dendritic Cell Subsets

    V. Dendritic Cells in Tumor Immunology

    VI. Dendritic Cells and Gene Therapy

    VII. Conclusions

    References

    10. DNA and Dendritic Cell-Based Genetic Immunization Against Cancer

    I. Introduction

    II. Background

    III. Recent Advances: Methods of Genetic Immunization

    IV. Preclinical Development and Translation to the Clinic

    V. Proposed and Current Clinical Trials

    VI. Future Directions

    References

    11. RNA-Transfected Dendritic Cells as Immunogens

    I. Introduction

    II. Advantages of Loading Dendritic Cells with Genetic Material

    III. Viral Versus Nonviral Methods of Gene Transfer 200

    IV. RNA Versus DNA Loading of Dendritic Cells

    V. RNA Loading of Dendritic Cells

    VI. Amplification of RNA Used to Load Dendritic Cells

    VII. Uses of RNA-Loaded Dendritic Cells

    VIII. Future Directions

    References

    PART IIc CYTOKINES AND CO-FACTORS

    12. In Situ Immune Modulation Using Recombinant Vaccinia Virus Vectors: Preclinical Studies to Clinical Implementation

    I. Introduction

    II. Generation of Cell-Mediated Immune Responses

    III. Cytokine Gene Transfer Studies in Antitumor Immunity

    IV. In Situ Cytokine Gene Transfer to Enhance Antitumor Immunity

    V. Future Directions

    VI. Conclusions

    References

    13. The Use of Particle-Mediated Gene Transfer for Immunotherapy of Cancer

    I. Introduction

    II. Background

    III. Recent Advances

    IV. Issues Regarding Evaluation in Clinical Trials

    V. Recent Clinical Trials

    VI. Potential Novel Uses and Future Directions

    References

    PART IId GENETICALLY MODIFIED EFFECTOR CELLS FOR IMMUNE-BASED IMMUNOTHERAPY

    14. Applications of Gene Transfer in the Adoptive Immunotherapy of Cancer

    I. Introduction

    II. Use of Gene-Modified Tumors to Generate Antitumor-Reactive T Cells

    III. Genetic Manipulation of T Cells to Enhance Antitumor Reactivity

    IV. Genetic Modulation of Dendritic Cells

    V. Summary

    References

    15. Update on the Use of Genetically Modified Hematopoietic Stem Cells for Cancer Therapy

    I. Introduction

    II. Human Hematopoietic Stem Cells as Vehicles of Gene Transfer

    III. Preclinical Studies of Gene Transfer into Hematopoietic Stem Cells

    IV. Applications of Genetically Manipulated Hematopoietic Stem Cells to the Therapy of Human Cancer

    V. Conclusions

    References

    Part III Oncogene-Targeted Gene Therapy

    16. Clinical Applications of Tumor-Suppressor Gene Therapy

    I. Introduction

    II. p53

    III. BRCA1

    IV. Onyx-015 Adenoviruses

    V. Summary and Future Work

    References

    17. Cancer Gene Therapy with Tumor Suppressor Genes Involved in Cell-Cycle Control

    I. Introduction

    II. p21WAF1/CIP1

    III. p16INK4

    IV. Rb

    V. p14ARF

    VI. p27Kip1

    VII. E2F-1

    VIII. PTEN

    IX. BRCA1

    X. VHL

    XI. FHIT

    XII. Apoptosis-Inducing Genes

    XIII. Conclusions

    References

    18. Cancer Gene Therapy with the p53 Tumor Suppressor Gene

    I. Introduction

    II. Vectors for Gene Therapy

    III. p53

    IV. Conclusions

    References

    19. Antisense Downregulation of the Apoptosis-Related Bcl-2 and Bcl-xl Proteins: A New Approach to Cancer Therapy

    I. The Bcl Family of Proteins and their Role in Apoptosis

    II. Downregulation of Bcl-2 Expression: Antisense Strategies

    References

    20. Gene Therapy for Chronic Myelogenous Leukemia

    I. Molecular Mechanisms Underlying Ph+ Leukemias

    II. Therapy

    III. Gene-Disruption Methods

    IV. Anti-bcr-abl Targeted Therapies

    V. Anti-bcr-abl Drug-Resistance Gene Therapy for CML

    VI. Conclusion

    References

    Part IV Manipulation of Drug Resistance Mechanisms by Gene Therapy

    21. Transfer of Drug-Resistance Genes into Hematopoietic Progenitors

    I. Introduction

    II. Rationale for Drug-Resistance Gene Therapy

    III. Methyltransferase-Mediated Drug Resistance

    IV. Cytidine Deaminase

    V. Glutathione-S-Transferase

    VI. Dual-Drug-Resistance Approach

    VII. Clinical Trials

    VIII. Conclusion

    References

    22. Multidrug-Resistance Gene Therapy in Hematopoietic Cell Transplantation

    I. Introduction

    II. P-Glycoprotein

    III. Targeting Hematopoietic Progenitor Cells for Genetic Modification

    IV. Expression of P-Glycoprotein in Murine Hematopoietic Progenitors

    V. Expression of P-Glycoprotein in Human Hematopoietic Progenitors

    VI. Results of Early Phase I Studies Using MDR1-Transduced Hematopoietic Cells

    VII. Overcoming Transduction Inefficiency

    VIII. MDR1 Gene Transfer into Humans: Recent Progress

    IX. Implication and Future of MDR1 Gene Therapy in Humans

    References

    23. Development and Application of an Engineered Dihydrofolate Reductase and Cytidine-Deaminase-Based Fusion Genes in Myeloprotection-Based Gene Therapy Strategies

    I. Introduction

    II. Fusion Genes

    III. Development of Clinically Applicable Gene Transfer Approaches

    IV. Preclinical Evidence for Myeloprotection Strategies

    V. Clinical Applications of Myeloprotection Strategies

    VI. Challenges

    References

    24. Protection from Antifolate Toxicity by Expression of Drug-Resistant Dihydrofolate Reductase

    I. Introduction

    II. Drug-Resistant Dihydrofolate Reductases

    III. Protection from Antifolate Toxicity In Vitro

    IV. Protection from Antifolate Toxicity In Vivo: Retroviral Transduction Studies

    V. Dihydrofolate Reductase Transgenic Mouse System for In Vivo Drug-Resistance Studies

    VI. Antitumor Studies in Animals Expressing Drug-Resistant Dihydrofolate Reductase

    VII. Antifolate-Mediated In Vivo Selection of Hematopoietic Cells Expressing Drug-Resistant Dihydrofolate Reductase

    VIII. Summary and Future Considerations

    References

    25. A Genomic Approach to the Treatment of Breast Cancer

    I. Introduction

    II. Toward a Genomic Approach to Therapy

    III. The Use of DNA Microarrays to Understand Drug Resistance

    IV. Effects of Genomic-Based Approaches on the Management of Breast Cancer Patients

    References

    Part V Anti-Aniogenesis and Pro-Apoptotic Gene Therapy

    26. Antiangiogenic Gene Therapy

    I. Introduction

    II. Angiogenesis and its Role in Tumor Biology

    III. Antiangiogenic Therapy of Cancer and the Role of Gene Therapy

    IV. Preclinical Models of Antiangiogenic Gene Therapy

    V. Inhibiting Proangiogenic Cytokines

    VI. Endothelial Cell-Specific Gene Delivery

    VII. Future Directions in Antiangiogenic Gene Therapy

    References

    27. VEGF-Targeted Antiangiogenic Gene Therapy

    I. Introduction

    II. Angiogenesis and Tumor Growth

    III. Gene Therapy for Delivery of Antiangiogenic Factors

    IV. Antiangiogenic Gene Therapy in the Experimental and Clinical Settings

    V. Vascular Endothelial Growth Factor and Receptors

    VI. Vascular Endothelial Growth Factor and Angiogenesis

    VII. Vascular Endothelial Growth Factor Inhibition by Gene Transfer

    VIII. Issues Regarding Clinical Translation of Antiangiogenic Gene Therapy

    IX. Conclusion

    References

    28. Strategies for Combining Gene Therapy with Ionizing Radiation to Improve Antitumor Efficacy

    I. Introduction

    II. Strategies Using Gene Therapy to Increase the Efficacy of Radiation Therapy

    III. Enhancing the Replicative Potential of Antitumor Viruses with Ionizing Radiation

    IV. Transcriptional Targeting of Gene Therapy with Ionizing Radiation (Genetic Radiotherapy)

    V. Summary and Future Directions

    References

    29. Virotherapy with Replication-Selective Oncolytic Adenoviruses: A Novel Therapeutic Platform for Cancer

    I. Introduction

    II. Attributes of Replication-Selective Adenoviruses for Cancer Treatment

    III. Biology of Human Adenovirus

    IV. Mechanisms of Adenovirus-Mediated Cell Killing

    V. Approaches to Optimizing Tumor-Selective Adenovirus Replication

    VI. Background: dl1520 (ONYX-015)

    VII. Clinical Trial Results with Wild-Type Adenovirus: Flawed Study Design

    VIII. A Novel Staged Approach to Clinical Research with Replication-Selective Viruses: dl1520 (ONYX-015)

    IX. Results from Clinical Trials with dl1520 (ONYX-015)

    X. Results from Clinical Trials with dl1520 (ONYX-015): Summary

    XI. Future Directions

    XII. Summary

    References

    30. E1A Cancer Gene Therapy

    I. Introduction

    II. HER2 Overexpression and E1A-Mediated Antitumor Activity

    III. Mechanisms of E1A-Mediated Anti-Tumor Activity

    IV. E1A Gene Therapy: Preclinical Models

    V. E1A Gene Therapy: Clinical Trials

    VI. Conclusion

    References

    Part VI Prodrug Activation Strategies for Gene Therapy of Cancer

    31. Preemptive and Therapeutic Uses of Suicide Genes for Cancer and Leukemia

    I. Introduction

    II. Therapeutic Uses of Suicide Genes

    III. Preemptive Uses of Suicide Genes in Cancer

    IV. Creation of Stable Suicide Functions by Combining Suicide Gene Transduction with Endogenous Gene Loss

    V. Preemptive Uses of Suicide Genes to Control Graft-Versus-Host Disease in Leukemia

    VI. Future Prospects for Preemptive Use of Suicide Genes

    References

    32. Treatment of Mesothelioma Using Adenoviral-Mediated Delivery of Herpes Simplex Virus Thymidine Kinase Gene in Combination with Ganciclovir

    I. Introduction

    II. Clinical Use of HSV-TK in the Treatment of Localized Malignancies

    III. Challenges and Future Directions

    References

    33. The Use of Suicide Gene Therapy for the Treatment of Malignancies of the Brain

    I. Introduction

    II. Retrovirus Vector for HSV-TK

    III. Adenovirus Vector for HSV-TK

    IV. Herpes Simplex Virus Vectors Expressing Endogenous HSV-TK

    V. Promising Preclinical Studies

    References

    34. Case Study of Combined Gene and Radiation Therapy as an Approach in the Treatment of Cancer

    I. Introduction

    II. Background of the Field

    III. Recent Advances in Herpes Simplex Virus-Thymidine Kinase Suicide Gene Therapy

    IV. Combined Herpes Simplex Virus-Thymidine Kinase Suicide Gene Therapy and Radiotherapy

    V. Issues Regarding Clinical Trials, Translation into Clinical Use, Preclinical Development, Efficacy, Endpoints, and Gene Expression

    VI. Potential Novel Uses and Future Directions

Product details

  • No. of pages: 534
  • Language: English
  • Copyright: © Academic Press 2002
  • Published: February 26, 2002
  • Imprint: Academic Press
  • eBook ISBN: 9780080491363

About the Editors

Edmund Lattime

Edmund C. Lattime is Professor of Surgery at the Robert Wood Johnson Medical School and Deputy Director, The Cancer Institute of New Jersey. Dr. Lattime studies tumor immunology and immunotherapy focusing on the tumor-host interaction and the tumor microenvironment. While faculty at Sloan Kettering and then Thomas Jefferson University, his translational studies led to the development and Phase I testing of a novel Vaccinia-GMCSF construct designed to enhance the development of antitumor immunity via infection/transfection of the tumor microenvironment. Based on his mechanistic studies of immune escape mechanisms, his group recently developed and is testing a poxvirus-based immunization strategy, which uses antigen encoding poxvirus delivered to the tumor microenvironment, in patients with locally-advanced pancreatic cancer.

Affiliations and Expertise

The Cancer Institute of New Jersey, New Brunswick, U.S.A.

Stanton Gerson

Stanton L Gerson is Director of the Case Comprehensive Cancer Center & the National Center for Regenerative Medicine at Case Western Reserve University and Director of University Hospitals Seidman Cancer Center in Cleveland. Dr. Gerson studies DNA repair, stem cells and cancer therapy. He showed that over-expression of the MGMT DNA repair gene could prevent cancer and that a mutant form of MGMT protects hematopoietic stem cells from chemotherapy using lentiviral gene therapy. He has interrogated MGMT, MMR and BER DNA repair pathways as targets for cancer therapy, and proposed that methoxyamine would block base excision repair used in combination with chemotherapy. Dr. Gerson also directed the initial use of mesenchymal stem cells (MSCs) in bone marrow transplantation & in gene therapy.

Affiliations and Expertise

Director of the Case Comprehensive Cancer Center and the National Center for Regenerative Medicine at Case Western Reserve University; Director of University Hospitals Seidman Cancer Center in Cleveland, OH.

Edmund Lattime

Edmund C. Lattime is Professor of Surgery at the Robert Wood Johnson Medical School and Deputy Director, The Cancer Institute of New Jersey. Dr. Lattime studies tumor immunology and immunotherapy focusing on the tumor-host interaction and the tumor microenvironment. While faculty at Sloan Kettering and then Thomas Jefferson University, his translational studies led to the development and Phase I testing of a novel Vaccinia-GMCSF construct designed to enhance the development of antitumor immunity via infection/transfection of the tumor microenvironment. Based on his mechanistic studies of immune escape mechanisms, his group recently developed and is testing a poxvirus-based immunization strategy, which uses antigen encoding poxvirus delivered to the tumor microenvironment, in patients with locally-advanced pancreatic cancer.

Affiliations and Expertise

The Cancer Institute of New Jersey, New Brunswick, U.S.A.

Stanton Gerson

Stanton L. Gerson received his M.D. at Harvard Medical School. He was a Resident in Medicine at the Hospital of the University of Pennsylvania, where he became a Fellow in Hematology-Oncology in 1980. He is an Edward Mallinckrodt Jr. Foundation Scholar, and is currently Chief, Division of Hematology/Oncology at Case Western Reserve Univeristy, where he has served since 1983. Dr. Gerson is a member of several major professional and scientific societies and is a principal investigator of funded grants for several philanthropic organizations. He is author or a contributor to over 200 research papers, abstracts, theses and book chapters. Since 1987, Dr. Gerson has been invited to be a guest lecturer at over 40 national and international conferences.

Affiliations and Expertise

Case Western Reserve University, Cleveland, Ohio, U.S.A.

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