Cancer Immunotherapy

List of Contributors

Chapter 1. Introduction

Acknowledgments

I Summary

II Historical Background

III The Challenge of Cancer

IV Parts of the Book

References

Section 1: Principles of Basic Immunology

Chapter 2. Components of the Immune System

I Overview

II Principal Tissues and Organs

III Cells of the Immune System

IV Immune Responses

V Lymphocyte Recognition of Antigen

VI Effector Functions

References

Chapter 3. Adaptive Immunity: B Cells and Antibodies

I Introduction to B Cells

II B-Cell Development

III Mature B Cells

IV Antibody Function

V B Cells and Cancer

VI Conclusions

References

Chapter 4. Adaptive Immunity: T Cells and Cytokines

I An Overview of the Events That Initiate an Adaptive Immune Response

II T-cell Activation: A Deeper Look

III The Differentiation of Naïve T Cells into Effector T Cells

IV The Significance of Polarizing Cytokines

V CD8+ T Cells Develop into Cytotoxic Lymphocytes

VI The Activities of Effector and Memory T Cells in Tissues

VII Two Major Types of Memory T Cells Remain after Antigen is Cleared

VIII The Challenges Faced by the Adaptive Immune System When Responding to Tumors

Further Reading

Chapter 5. Dendritic Cells: Antigen Processing and Presentation

I Dendritic Cells: Introduction

II Antigen Processing and Presentation

III MHC Class I

IV MHC Class II

V Alternate Pathways of Antigen Presentation

VI Dendritic Cell Subsets and Specialized Functions

VII Human DC Subsets

VIII Conclusions

References

Chapter 6. Mucosal Immunity

I Overview

II Mucosal Surfaces are the Major Portals of Entry for Antigen

III Epithelial Barrier

IV Inductive and Effector Sites in the Mucosa-associated Lymphoid Tissue

V The Microbiome and Mucosal Surfaces

VI Tolerance to Dietary Antigen and the Microbiome

References

Section 2: Principles of Cancer Immunobiology

Chapter 7. Cancer Immunoediting: From Surveillance to Escape

Acknowledgments

I Introduction

II History of Cancer Immune Surveillance and Cancer Immunoediting

III Mouse Models of Cancer Used in the Establishment of the Three ES

IV Cancer Immunoediting in Humans

References

Chapter 8. Immunosurveillance: Innate and Adaptive Antitumor Immunity

I Introduction

II Innate Antitumor Responses

III Innate Immune Cells^∗

IV Adaptive Antitumor Responses

V Adaptive Immunity in Immunosurveillance

VI Targets of Antitumor T-Cell Responses

VII Antitumor Effector Mechanisms: Cytokines^∗

VIII Antitumor Effector Mechanisms: Cytotoxic Mechanisms

IX The Interplay of Innate and Adaptive Antitumor Immunity

X Conclusion

References

Chapter 9. Immunological Sculpting: Natural Killer-Cell Receptors and Ligands

I Introduction

II NK Education, Licensing, and Priming

III How Receptor: Ligand Interactions Trigger Cell Lysis

IV Receptors for MHC I and MHC I-Related Molecules

V Conclusion

References

Chapter 10. Th17 Cells in Cancer

I Th17 Definition

II Generation, Cytokine Profile and Genetic Control of Th17 Cells

III Th17-Cell Plasticity

IV Th17-Cell Stemness

V Th17 Cancer Immunity

VI Th17 Associated Cytokines and Carcinogenesis

VII Conclusion

References

Chapter 11. Immune Escape: Immunosuppressive Networks

I Introduction

II Dysfunctional T-Cell Differentiation

III T-Cell Exhaustion in Cancer

IV Balance of Extracellular Adenosine and ATP in the Tumor: A Fundamental Regulator of Immune Reactivity

V Chemical Barriers Faced by T Cells in the Tumor

VI Conclusions

References

Section 3: Introduction to Cancer Therapeutics

Chapter 12. Principles of Cytotoxic Chemotherapy

I Introduction

II Clinical Use of Chemotherapy

III Tumor Growth and Its Impact on Chemotherapy Use

IV General Principles of Chemotherapy Use

V Classes of Chemotherapies and Their Function

VI Conclusions

References

Chapter 13. Pharmacokinetics and Safety Assessment

I Introduction

II Concepts in Pharmacokinetics (PK)

III Concepts in Toxicology

IV Clinical Concerns for Pharmacology and Safety

V Conclusions

References

Chapter 14. Monoclonal Antibodies for Cancer Therapy and Prevention: Paradigm Studies in Targeting the neu/ERBB2/HER2 Oncoprotein

Acknowledgments

I Introduction

II ERBB2/HER2/NEU in Human Disease

III ERBB2/NEU as a Therapeutic Target

IV Conclusions

References

Chapter 15. Genetic Vaccines against Cancer: Design, Testing and Clinical Performance

Acknowledgments

I Introduction

II DNA Vaccines

III Messenger RNA Vaccines

IV Virus-like Particle Vaccines

V Plant Viral Particles and Their Derivatives as Vaccines

VI PVX-based Plant Viral Particle (PVP) Conjugate Vaccines

VII Vaccination of Human Subjects

VIII Quantitative and Qualitative Features of Vaccine-induced T-cell Responses

IX Clinical Trials of DNA Vaccines

X Immune Responses to DNA Vaccination

XI Immunotherapy Trial Endpoints and Choice of Clinical Settings

XII Immunological Assay Harmonization

References

Chapter 16. Comprehensive Immunomonitoring to Guide the Development of Immunotherapeutic Products for Cancer

I Immunotherapy of Cancer

II Immunomonitoring

III Monitoring of Unwanted Immune Reactions

IV Harmonization of Immune Monitoring

V Immunoguiding

References

Section 4: Strategies of Passive and Active Immunotherapy

Chapter 17. Adoptive T-cell Therapy: Engineering T-cell Receptors

I Early Trials of Adoptive T-cell Therapy

II Isolating TCRs for Gene Transfer

III Antigen Choice for TCR Therapy

IV Engineering to Improve TCR Activity

V TCR Delivery

VI Clinical Trials

VII Overcoming Tumor Microenvironment Inhibition of T-Cell Function

VIII Conclusion

References

Chapter 18. Dendritic Cell Vaccines: Sipuleucel-T and Other Approaches

Acknowledgments

I Generating a Cancer Vaccine

II Dendritic Cells: Critical for Generating an Immune Response^∗

III History and Basic Biology of DC Vaccines^∗∗

IV Sipuleucel-T: A Dendritic Cell Vaccine for Prostate Cancer

V Improving DC Vaccines

VI Improving DC Vaccines: Combination Treatment Approaches

VII Immune Checkpoint Blockade

VIII Selected DC Vaccines in Clinical Development

IX Conclusion

Disclaimer

References

Chapter 19. Antibodies to Stimulate Host Immunity: Lessons from Ipilimumab

I Introduction

II Preclinical Development of CTLA-4 Blockade

III Clinical Development of Ipilimumab

IV Lessons Learned during the Clinical Development of Ipilimumab

V Clinical Testing of Ipilimumab in Diseases Other Than Melanoma

VI Outstanding Questions and Future Directions

VII Conclusions

References

Chapter 20. Recombinant TRICOM-based Therapeutic Cancer Vaccines: Lessons Learned

I The Choice of Recombinant Poxviral Vectors

II Development of Preclinical Models

III T-Cell Co-stimulation: Development of Tricom Vectors

IV Clinical Trials

V The Importance of Clinical Trial Design in Vaccine Therapy

VI Prostate Cancer Clinical Trials

VII Tricom Vaccines also Contain Tumor Antigen Agonist Epitopes

VIII Tricom Vaccination Affects Tumor Growth Rates

IX Intratumoral Vaccination: Clinical Studies

X Combination Therapies—Preclinical Studies

XI Combination Therapies—Clinical Studies

XII Lessons Learned and Moving Forward

References

Chapter 21. Adjuvant Strategies for Vaccines: The Use of Adjuvants within the Cancer Vaccine Setting

I Introduction

II Why Adjuvants Work

III Tumor-associated Antigens and the Need for Adjuvants in Cancer Vaccines

IV Immunostimulatory Adjuvants

V Particulate vaccine adjuvants

A Emulsions

VI Dc Priming in Vivo Versus Ex Vivo

VII Conclusions

References

Section 5: Improving Immunotherapeutic Responses

Chapter 22. Epigenetic Approaches: Emerging Role of Histone Deacetylase Inhibitors in Cancer Immunotherapy

I Introduction

II Tumor-Induced Tolerance is a Significant Barrier for Cancer Immunotherapy

III Epigenetics and Cancer

IV Role of Specific HDACs in Immunity: Molecular Signaling and Pathways

V HDIs

VI Controversy: Are HDIs Pro- or Anti-Inflammatory Drugs?

VII Conclusions

References

Chapter 23. Molecular Profiling of Immunotherapeutic Resistance

Acknowledgments

I Introduction—The Bedside to Bench and Back (BB&B) approach to tumor immunology: In Vivo Veritas

II Strategies to Identify Molecular Pathways Associated With Immunoresponsiveness and Immunoresistance Following Immunotherapy

III The Emerging of a More Falsifiable, Informative and Preferred Theory: The Immunologic Constant of Rejection (ICR)

IV Understanding the Mechanism of Actions of Immunotherapeutic Agents through Gene Expression Profiling

V Understanding the Immune-Mediated Tumor Rejection through Gene Expression Profiling

VI Predicting Immune Responsiveness to Immunotherapeutics Through Gene Expression Profiling

VII Linkage Between Autoimmunity and Tumor Rejection

VIII Understanding the Origin of the Immune-Signature and Future Directions

IX Conclusion

References

Chapter 24. Immune Stimulatory Features of Classical Chemotherapy

Acknowledgments

I Introduction

II The Immunopotentiating Effect of Cancer Chemotherapy

III How Can We Use and Enforce the Immunogenic Properties of Chemotherapeutic Drugs?

IV Conclusions

References

Chapter 25. Immunotherapy and Cancer Therapeutics: A Rich Partnership

Acknowledgments

I Introduction: Why Integrate Cancer Drugs with Tumor Immunotherapy?

II Chemotherapy and Tumor Immunity

III Clinical Trials of Chemoimmunotherapy

IV Immune Modulation with Therapeutic Monoclonal Antibodies

V Immune Modulation with Biologically Targeted Therapy

VI Conclusions

Conflict of Interest

References

Section 6: Targeting Strategies to Defeat Immune Suppression

Chapter 26. JAK/STAT Signaling in Myeloid Cells: Targets for Cancer Immunotherapy

I Introduction

II Overview of JAK/STAT Signaling

III JAK/STAT3 Signaling in Myeloid Cell-Mediated Immunosuppression

IV Targeting JAK/STAT3 Signaling in Myeloid Cells

V Concluding Remarks

References

Chapter 27. Tumor-associated Macrophages in Cancer Growth and Progression

Acknowledgments

I Introduction

II Macrophage Polarization

III Macrophage Recruitment at the Tumor Site

IV Tam Express Selected M2 Protumoral Functions

V Modulation of Adaptive Immunity by TAM

VI Targeting TAM

VII Concluding Remarks

References

Chapter 28. Tumor-induced Myeloid-derived Suppressor Cells

Acknowledgments

I Introduction

II Mouse and Human MDSC are a Heterogeneous Mixture of Immature Myeloid Cells

III MDSC use Diverse Suppressive Mechanisms to Inhibit Antitumor Immunity

IV Inflammation Drives MDSC Accumulation and Suppression

V MDSC Turnover

VI Therapeutic Approaches for Reducing MDSC-Mediated Immune Suppression

VII Conclusions

References

Chapter 29. HyperAcute Vaccines: A Novel Cancer Immunotherapy

Acknowledgments

I Background and Historical Perspective

II Preclinical Development of Hyperacute^® Immunotherapy

III Clinical Development of HyperAcute Immunotherapy

IV Conclusions

References

Chapter 30. Tumor Exosomes and Their Impact on Immunity and Cancer Progression

I Introduction

II Discovery and Definition of Exosomes

III Biogenesis and Composition of Exosomes from Normal and Tumor Cells

IV Separation and Handling of Exosomes

V Immunosuppressive Role of Tumor Exosomes

VI Role of Tumor-derived Exosomes in Cancer Progression

VII Mechanisms of Interaction with Target Cells

VIII Tumor-derived Exosomes and Cancer Therapies

IX Tumor-derived Exosomes as Diagnostic Agents

X Conclusion and Future Needs

References

Chapter 31. Galectins: Key Players in the Tumor Microenvironment

Acknowledgments

I Galectins: Definition, Structure and Function

II Galectin–Glycan Interactions as Key Modulators of Tumor Immunity

III Galectins in the Tumor Microenvironment: Non-Immune Related Functions

IV Emerging Roles of Galectins in Tumor Chemoresistance

V Galectin Inhibitors as Potential Anticancer Agents

VI Conclusions

Conflict of Interest

References

Chapter 32. IDO in Immune Escape: Regulation and Therapeutic Inhibition

Acknowledgments

I Introduction

II Tryptophan Catabolism by IDO: A Historical Conundrum

III IDO Dysregulation in the pathogenesis of cancer

IV 1MT as a Therapeutic Prototype

V Conclusions

Recommended Resources Websites

Further Reading

References

Chapter 33. IDO Pathway: Effect on Foxp3⁺ Tregs and Cancer

I Introduction

II IDO Is a Natural Mechanism of Peripheral Tolerance

III IDO Expression in Human Tumors and Tumor-Draining LNs

IV IDO and Tregs

V Downstream Mechanisms of IDO

VI Induction of IDO by Tregs

VII IDO-Pathway Inhibitor Drugs as a Potential Strategy to Reduce Treg-Mediated Suppression

Conflict of Interest

References

Chapter 34. Arginase, Nitric Oxide Synthase, and Novel Inhibitors of L-arginine Metabolism in Immune Modulation

Acknowledgments

I Introduction

II Nitric Oxide Synthase (NOS): Genes, Regulation, and Activity

III Arginase (ARG): Genes, Regulation, and Activity

IV Immunoregulatory Activities of ARG and NOS

V Mechanisms of NOS-Dependent Immunoregulation

VI Mechanisms of ARG-Dependent Immunoregulation

VII ARG and NOS Cooperation in Immunoregulation: An Emerging Concept

VIII Peroxynitrite Generation

IX Peroxynitrite and Autoimmunity

X Hydrogen Peroxide Generation

XI Is there a Physiological Role for L-Arg Metabolism in the Control of Immunity?

XII NOS in Cancer

XIII ARG in Cancer

XIV ARG and NOS Inhibitors: A Novel Class of Immune Adjuvants?

XV Conclusions and Perspectives

Selected Internet URLs

Disclaimer

References

Index