CANCER IMMUNOLOGY : bench to bedside immunotherapy of cancers.

Preface
Acknowledgments
Contents
Contributors
Abbreviations
1: Frontiers in Cancer Immunotherapy
	1.1	 Introduction
	1.2	 Innate Cells as Initiators of the Adaptive Immune Response
	1.3	 Cellular Immunotherapy
	1.4	 Active and Passive Immunotherapy
		1.4.1	 Active Immunotherapy
		1.4.2	 Nonspecific Immunotherapy
	1.5	 Stimulation of Responses In Vivo
	1.6	 Adoptive Immunotherapy
	1.7	 Cancer Vaccines
		1.7.1	 Dendritic Cells
		1.7.2	 Physical Barriers, Tumor Stroma, and Vessels
	1.8	 Mechanisms of Tumor-Induced Tolerance/Escape from the Immune System
		1.8.1	 Treg Cells
		1.8.2	 Myeloid-Derived Suppressor Cells
		1.8.3	 Macrophages
	1.9	 Candidates for Immunotherapy in Oncology
	1.10	 Combination Immunotherapy
		1.10.1	 Chemotherapy and mAb
		1.10.2	 Chemotherapy and Active Specific Immunotherapy
		1.10.3	 Chemotherapy and Adoptive Lymphocyte Immunotherapy
		1.10.4	 Immunotherapy with Radiation Therapy
	1.11	 Humoral Immunotherapy
	1.12	 Concluding Remarks
	References
2: Novel Strategy of Cancer Immunotherapy: Spiraling Up
	2.1	 Introduction
	2.2	 Natural Killer Cells: The Key Effectors of Innate Immunity
	2.3	 Adoptive IL-2/LAK (or CIK) Therapy of Cancer
	2.4	 Tumor-Infiltrating Lymphocytes (TILs) in Cancer Immunotherapy
	2.5	 Autologous Vaccines on the Base of Dendritic Cells (DC Vaccines)
	2.6	 Advantages of Combined Implication of DC Vaccines and Activated Lymphocytes
	2.7	 Combination of Immune Checkpoint Blockade and Adoptive Immunotherapy
	2.8	 CART Cells
	2.9	 Spiral Up
	2.10	 Concluding Remarks
	References
3: Personalized Prevention Strategies to Defeat Cancer
	3.1	 Introduction
	3.2	 The Thioredoxin1 System
	3.3	 The CD30 System
	3.4	 The Functional Link Between Trx1 and CD30 Systems
	3.5	 The Polymorphisms of KIRs, FcγRIIa-131H/R, and FcγRIIIa-158V/F Could Be Clinical Stratification Parameters to Personalize the Prognostic Trx1/CD30 Biomarkers of the Early Risk in Tumor Disease or Progression
	3.6	 The Trx1/CD30 Double Target Is a Real Weapon to Defeat Cancer
	3.7	 KIR and FcγRIIa and FcγRIIIa Polymorphisms Are Biomarkers of Low/Moderate/High Risk of Cancer Disease or Progression
	3.8	 Concluding Remarks
	References
4: Tumor Antigen Identification for Cancer Immunotherapy
	4.1	 Introduction
	4.2	 Tumor Antigens
	4.3	 Approaches to Identify Tumor Antigens
		4.3.1	 Prediction-Based Identification
			4.3.1.1	 Antigen Identification
			4.3.1.2	 In Silico Peptide Prediction
			4.3.1.3	 Validation of Antigen Presentation and Immunogenicity
		4.3.2	 Forward Immunology in Tumor Antigen Identification
			4.3.2.1	 Genome Sequencing
			4.3.2.2	 Isolation of HLA-Peptide Complex
			4.3.2.3	 Sequencing of Neopeptide
	4.4	 Clinical Utility of Tumor Antigen Identification
	4.5	 Concluding Remarks
	References
5: Strategies to Target Tumor Immunosuppression
	5.1	 Introduction: The Balance of Immune Surveillance in the Tumor
	5.2	 The Balance Is Tilted: Mechanisms of Tumor Immune Escape
		5.2.1	 Tolerance Mechanisms
			5.2.1.1	 CD4+ Helper T Cells and CD8+ Cytotoxic T Lymphocytes: Negative Polarization and Apoptosis
			5.2.1.2	 Defects in the Antigen Presentation Process
		5.2.2	 Immunosuppression Mechanisms
			5.2.2.1	 Cancer-Associated Fibroblasts (CAFs)
			5.2.2.2	 Myeloid-Derived Suppressor Cells (MDSCs)
			5.2.2.3	 Regulatory T Cells (Tregs)
			5.2.2.4	 Tumor-Associated Macrophages (TAMs)
			5.2.2.5	 Tumor-Derived Immunosuppressive Factors
				Cytokines
				Enzymes
				Negative Regulatory Factors
				Endothelin Receptors
	5.3	 Shifting the Balance: Strategies to Target Tumor Immunosuppression
		5.3.1	 Strategies Targeting Homing of Effector T Cells
			5.3.1.1	 Local Tumor Irradiation
			5.3.1.2	 Blockade of Endothelin Receptors
			5.3.1.3	 Taxane-Based Chemotherapy
			5.3.1.4	 Antibody-Mediated Targeting of Effector CTLs
		5.3.2	 Strategies Targeting the Activity of Effector T Cells
			5.3.2.1	 Circumventing Activity of Suppressive Immune Populations: Depletion or Inactivation Therapy
			5.3.2.2	 Immunostimulatory Cytokines: Cytokine Therapy
			5.3.2.3	 Blockade of Negative Regulatory Factors: Antibody Therapy
	5.4	 Concluding Remarks
	References
6: Overcoming Cancer Tolerance with Immune Checkpoint Blockade
	6.1	 Introduction
	6.2	 Neoantigens: Targets for the Immune System
	6.3	 Cytotoxic T-Lymphocyte-Associated Antigen-4 (CTLA-4): The First Checkpoint Pathway to Demonstrate Clinical Benefit
		6.3.1	 CTLA-4 Function
		6.3.2	 Tremelimumab
		6.3.3	 Toxicity
	6.4	 Programmed Death 1 (PD-1) Pathway
		6.4.1	 Function
		6.4.2	 PD-1 Pathway in Cancer
		6.4.3	 PD-1 Blockade
		6.4.4	 Nivolumab
		6.4.5	 Pembrolizumab
		6.4.6	 PD-L1 Blockade
		6.4.7	 Atezolizumab
		6.4.8	 Durvalumab
		6.4.9	 Avelumab
	6.5	 Immune-Related Response Criteria
	6.6	 CTLA-4 Blockade Monotherapy
		6.6.1	 Ipilimumab
			6.6.1.1	 Ipilimumab in Uveal Melanoma
		6.6.2	 Phase III Trials of Checkpoint Inhibitors in Melanoma
		6.6.3	 Adjuvant Checkpoint Inhibitors
	6.7	 Checkpoint Inhibitors as Combination Therapy
		6.7.1	 Checkpoint Inhibitors and Chemotherapy
			6.7.1.1	 PD-1/PD-L1 Inhibitors and Chemotherapy
		6.7.2	 Checkpoint Inhibitors and Radiation
	6.8	 Combination Immunotherapy
		6.8.1	 CTLA-4 Blockade and Vaccination
		6.8.2	 PD-1/PD-L1 and Vaccination
		6.8.3	 CTLA-4 Blockade and Cytokine Therapy
		6.8.4	 Combination Checkpoint Blockade
	6.9	 Other Checkpoint Pathways Under Development
		6.9.1	 Lymphocyte Activation Gene-3 (LAG-3)
		6.9.2	 4-1BB
		6.9.3	 OX-40
		6.9.4	 Glucocorticoid-Induced TNFR-Related Protein (GITR)
		6.9.5	 CD40
		6.9.6	 TIM-3
		6.9.7	 TGN1421: A Cautionary Tale
	6.10	 Conclusion
	References
7: Gene Therapy and Genetic Vaccines
	7.1	 Introduction
	7.2	 Gene Therapies
		7.2.1	 Gene Delivery Methods
			7.2.1.1	 Viral Vector
				Adenovirus
				Adeno-Associated Virus Vector (AAVVs)
				Herpes Simplex Virus Type 1 Vectors (HSVVs)
				Retrovirus Vectors (RVVs)
				Lentivirus Vectors (LVVs)
				Poxviruses
			7.2.1.2	 Nonviral Vector
				Cationic Polymers
				Lipid Polymers
		7.2.2	 Gene Therapy Strategies
			7.2.2.1	 Tumor Cell Killing Therapies
				Suicide Gene
				Apoptosis
				Antiangiogenic
				Tumor Suppressor Insertion
			7.2.2.2	 Oncogene Blocking
			7.2.2.3	 Antitumor Immunity Enhancement
	7.3	 Genetic Vaccines
		7.3.1	 DNA Vaccines
		7.3.2	 RNA Vaccines
		7.3.3	 Virus-Based Vaccines
		7.3.4	 Prime-Boost Cancer Vaccines
	References
8: Hematopoietic Stem Cell Transplantation and Lymphodepletion for the Treatment of Cancer
	8.1	 Introduction
	8.2	 Hematopoietic Stem Cell Transplantation (HSCT)
		8.2.1	 Sources of Hematopoietic Stem Cells (HSCs)
		8.2.2	 Autologous and Allogeneic HSCT
		8.2.3	 Graft-Versus-Host Disease and the Graft-Versus-Tumor Effect
	8.3	 Conditioning Regimens Before Hematopoietic Stem Cell Transplantation (HSCT)
		8.3.1	 Myeloablative Conditioning
		8.3.2	 Reduced-Intensity and Non-myeloablative Conditioning
	8.4	 Lymphodepletion for the Treatment of Solid Tumors
	8.5	 Reconstitution of the T-Cell Repertoire After Lymphodepletion
		8.5.1	 Lymphodepletion-Induced T-Cell Thymopoiesis Is Important for Reconstitution of the T-Cell Repertoire
		8.5.2	 Lymphodepletion-Induced Homeostatic Proliferation as Strategy to Augment Antitumor Immunity
		8.5.3	 Use of Animal Models to Address Immunological Effects of Lymphodepletion
	8.6	 Concluding Remarks
	References
9: Recent Advances in Haploidentical Hematopoietic Cell Transplantation for Pediatric Hematologic Malignancies
	9.1	 Introduction
	9.2	 Advantages of Haploidentical Hematopoietic Cell Transplantation
	9.3	 Lessons from Adult Haploidentical Hematopoietic Cell Transplantation Studies
	9.4	 Evolution of T Cell Depletion Strategies in Pediatric Haploidentical Hematopoietic Cell Transplantation
		9.4.1	 CD34+ Megadose
		9.4.2	 CD3/CD19 Depletion
		9.4.3	 αβ T Cell and CD19 B Cell Depletion
		9.4.4	 Donor Selection Considerations in T Cell-Depleted Haploidentical Transplants
	9.5	 Pediatric Haploidentical Hematopoietic Cell Transplantation with T Cell-Replete Grafts
		9.5.1	 Post-transplant Cyclophosphamide (PT-CY)
		9.5.2	 The Chinese Experience with GIAC Protocol
	9.6	 Conclusion
	References
10: Combination of Chemotherapy and Cytokine Therapy in Treatment of Cancers
	10.1	 Introduction
	10.2	 Immune Response in the Control of Cancer
		10.2.1	 Cancer Immunoediting Theory
		10.2.2	 Tumors Escape from the Host Immune Response
			10.2.2.1	 Regulatory T Lymphocytes
			10.2.2.2	 Myeloid-Derived Suppressor Cells and Their Immunosuppressive Activity
	10.3	 Immunotherapy of Cancer
		10.3.1	 Enhancing Antitumor Immunity Using Cytokines
	10.4	 Overcoming Tumor Resistance and the Use of Chemotherapeutic Agents
		10.4.1	 Chemotherapy Plus Immunotherapy
		10.4.2	 Rationale for Drug Selection
	10.5	 Combined Therapies
		10.5.1	 Preclinical Experience
		10.5.2	 What Have We Learned from the Clinical Practice?
	10.6	 Concluding Remarks
	References
11: Type I Interferons: History and Perspectives as Immunotherapeutic Agents Against Cancer
	11.1	 Introduction
	11.2	 Role of Type I IFNs in Malignant Transformation
	11.3	 Role of Type I IFNs in Cancer Immunoediting
		11.3.1	 Type I IFNs and Natural Killer (NK) Cells
		11.3.2	 Type I IFNs and Dendritic Cells (DCs)
	11.4	 Immunotherapeutic Approaches
		11.4.1	 Toll-Like Receptors (TLRs) Agonists
		11.4.2	 RIG-Like Receptors (RLRs) Agonists
		11.4.3	 Stimulators of Interferon Genes (STING) Agonists
	11.5	 Concluding Remarks
	References
12: T-Cell Immunotherapy: From Synthetic Biology to Clinical Practice
	12.1	 Introduction
	12.2	 T-Cell Responses to Cancer
	12.3	 From Polyclonal to Single-Specificity Effector T-Cells
	12.4	 From MHC to Antibody-Based Recognition: Therapy with T-Cells Expressing CARs
		12.4.1	 History of CAR Development
		12.4.2	 CAR-T Design
		12.4.3	 Inclusion of T-Cell Co-stimulatory Moieties
		12.4.4	 CAR-T Technological Improvements
			12.4.4.1	 Safety Switches
			12.4.4.2	 Deletion of Native Surface Proteins in CART-Cells
			12.4.4.3	 Switch-Controlled CARs
			12.4.4.4	 Reducing CART Immunogenicity
			12.4.4.5	 Mitigating Tumor Antigen Escape
		12.4.5	 Vectors Used for CAR Expression
		12.4.6	 Impact of T-Cell Culture and Expansion Techniques
		12.4.7	 Clinical Advances in CAR Therapy
	12.5	 Concluding Remarks
	References
13: Role of γδ T Lymphocytes in Cancer Immunosurveillance and Immunotherapy
	13.1	 Introduction
	13.2	 TCRγδ Repertoires and Functions
		13.2.1	 Mouse γδ T-Cell Subsets
		13.2.2	 Human γδ T-Cell Subsets
	13.3	 γδ T-Cell Activation: TCRγδ Agonists
		13.3.1	 Phosphoagonists (Phosphoantigens)
			13.3.1.1	 Phosphoagonists Produced by Microorganisms and Eukaryotic Cells
			13.3.1.2	 Phosphoagonist Intermediates of Isoprenoid Biosynthetic Pathways
		13.3.2	 Aminobisphosphonates
		13.3.3	 Alkylamines
		13.3.4	 Protein Ligands
			13.3.4.1	 Self-Ligands
				T10/T22
				F1-ATPase
				ULBP4
				MICA
				EPCR
				Heat-Shock Proteins (HSPs)
			13.3.4.2	 Non-Self-Ligands
	13.4	 γδ T-Cell Activation: Costimulatory Molecules
		13.4.1	 CD27
		13.4.2	 CD28
		13.4.3	 Fc Receptors: CD16
	13.5	 γδ T-Cell Activation via Natural Killer Receptors (NKRs)
		13.5.1	 NKG2D
		13.5.2	 NKG2A
		13.5.3	 Natural Cytotoxicity Receptors (NCRs)
		13.5.4	 DNAM-1
	13.6	 Tumor Cell Recognition by γδ T-Cells: TCRs Versus NKRs
	13.7	 γδ T-Cell Responses to Tumors
		13.7.1	 Antitumor Properties
		13.7.2	 Pro-Tumor Properties
	13.8	 γδ T-Cell Modulation in Cancer Clinical Trials
	13.9	 Concluding Remarks
	References
14: Adoptive T-Cell Therapy: Optimizing Chemokine Receptor-Mediated Homing of T-Cells in Cancer Immunotherapy
	14.1	 Introduction
	14.2	 T-Cell Infiltration Correlates with Prognosis
	14.3	 Adoptive T-Cell Therapy
	14.4	 Challenges in Adoptive T-Cell Therapy
	14.5	 Chemokines
	14.6	 Role of Chemokines in Directing Tissue Trafficking in Tumors
	14.7	 Overexpression of Chemokine Receptors in Engineered Lymphocytes to Be Used for Cancer Immunotherapy
	14.8	 Concluding Remarks
	References
15: Monoclonal Antibodies for Cancer Immunotherapy
	15.1	 Introduction
	15.2	 Structural and Functional Features of Antibodies
	15.3	 Natural Antibodies in Cancer
	15.4	 Finding an Appropriate Antibody Target for Cancer Therapy
		15.4.1	 Characteristics of a Favorable Cell Surface Antigen
		15.4.2	 Classification of Cancer Antigens
		15.4.3	 Target Identification Approaches
			15.4.3.1	 Genomics
			15.4.3.2	 Transcriptomics
			15.4.3.3	 Proteomics
			15.4.3.4	 Antibody-Based Technologies
	15.5	 Molecular Mechanisms Involved in Monoclonal Antibody-Based Therapy
		15.5.1	 Direct Tumor Cell Elimination
		15.5.2	 Harnessing the Potential Capacity of Immune System to Eliminate Tumors
			15.5.2.1	 Antibody-Dependent Cell-Mediated Cytotoxicity
			15.5.2.2	 Complement-Dependent Cytotoxicity
			15.5.2.3	 Promotion of Tumor Antigen Cross-Presentation
			15.5.2.4	 Targeting Immunomodulatory Receptors
		15.5.3	 Targeting Tumor Stroma and Vasculature
	15.6	 Engineered Antibodies
		15.6.1	 Murine Monoclonal Antibodies
		15.6.2	 Chimeric and Humanized Monoclonal Antibodies
		15.6.3	 Fully Human Monoclonal Antibodies
			15.6.3.1	 Human Monoclonal Antibodies from Transgenic Mice
			15.6.3.2	 Human Monoclonal Antibodies Created Through Phage Display Technology
		15.6.4	 Antibody Fragments
		15.6.5	 Bispecific Antibodies (BsAbs)
		15.6.6	 Antibody Fusion Constructs
		15.6.7	 Improvement in Antibody Function
	15.7	 Evaluation of Antibody Efficacy
		15.7.1	 Preclinical Evaluations
		15.7.2	 Clinical Evaluations
	15.8	 Clinically-Approved Monoclonal Antibodies
		15.8.1	 Trastuzumab
		15.8.2	 Bevacizumab
		15.8.3	 Rituximab
		15.8.4	 Therapeutic Monoclonal Antibodies Approved by Non-FDA Organizations
	15.9	 Monoclonal Antibodies Currently Undergoing Clinical Trials
	15.10	 Combinational Monoclonal Antibody-Based Modalities
		15.10.1	 Combination with Chemotherapy
		15.10.2	 Combination with Radiotherapy
		15.10.3	 Combination with Other Immunotherapeutic Methods
		15.10.4	 Other Combinational Approaches
	15.11	 Current Limitations in Monoclonal Antibody-Based Therapies
		15.11.1	 Tumor Escape
		15.11.2	 Relatively Low Single Agent Activity
		15.11.3	 Low Tissue Penetration
		15.11.4	 Fc–Fc Receptor Interactions and Associated Limitations
		15.11.5	 High Production Cost
	15.12	 Concluding Remarks
	References
16: Toll-Like Receptor Pathway and Its Targeting in Treatment of Cancers
	16.1	 Introduction
	16.2	 TLRs Play Important Roles in Human Carcinogenesis
	16.3	 TLR Regulates Tumor-Induced Immune System Response
	16.4	 TLR Targeting May Inhibit Cancer Cell Proliferation
	16.5	 TLR Triggering Can Promote Antitumor Response
	16.6	 Regulatory Effects of TLRs on PI3K/Akt Signaling Controlling Tumor Progression
	16.7	 TLR-Mediated Hypoxia-Inducible Factor 1 (HIF-1) Expression Leads to Tumor Progression
	16.8	 Role of TLRs in Tumor Cell Lysis and Apoptosis
	16.9	 TLRs Are Involved in Tumor Metastasis
	16.10	 Concluding Remarks
	References
17: Recent Advances in the Use of NK Cells Against Cancer
	17.1	 Introduction
	17.2	 NK Cell Basics
		17.2.1	 How Do NK Cells Become Activated to Kill?
		17.2.2	 Why Should NK Cells Be Targeted as Anticancer Agents?
	17.3	 Challenges Involved in Targeting NK Cells
		17.3.1	 How Many NK Cells Are in Cancer Patients and Tumors?
		17.3.2	 What Is the Functionality of NK Cells in Tumors?
	17.4	 Cancer Immunotherapies Involving NK Cells
	17.5	 Adoptive NK Cell Transfer
		17.5.1	 How Can We Produce Large Numbers of Activated NK Cells?
	17.6	 Autologous Transfer of NK Cells
	17.7	 Allogeneic Transfer of NK Cells
	17.8	 NK Cell Lines for Allogeneic Adoptive Transfer
	17.9	 NK Cells, ADCC, and mAb Therapy
	17.10	 Cytokines and Promoting NK Activation/Stopping Inhibition
	17.11	 Concluding Remarks
	References
18: Dendritic Cell Vaccines for Cancer Therapy: Fundamentals and Clinical Trials
	18.1	 Introduction
	18.2	 Strategies for Developing Clinical-Grade DC Vaccines
	18.3	 Routes of Administration
	18.4	 DC Vaccine for Prostate Cancer
	18.5	 DC Vaccine for Melanoma
	18.6	 DC Vaccine for Colorectal Cancer
	18.7	 DC Vaccine for Nervous Tissue Cancer
	18.8	 Concluding Remarks
	References
19: Tumor-Associated Macrophages and Cancer Development
	19.1	 Introduction
	19.2	 Cancer and Inflammation
	19.3	 Development of Myeloid Lineage Cells Including Macrophages
	19.4	 Characteristics of TAMs
	19.5	 “Reeducating” TAMs to Cytotoxic Phenotype
	19.6	 Concluding Remarks
	References
20: Exosomes: Pros and Cons for Fighting Cancer
	20.1	 Introduction
	20.2	 Tumor Cell-Derived Exosomes
	20.3	 Exosomes Secreted by Dendritic Cells
	20.4	 Diagnostic Application of Exo
	20.5	 New Perspectives of Using Exo for Therapy
	20.6	 Concluding Remarks
	References
21: Photodynamic Therapy and Antitumor Immune Response
	21.1	 Introduction
	21.2	 Photodynamic Therapy
	21.3	 DAMPs (Damage-Associated Molecular Patterns) and Tumor Ablative Therapies
	21.4	 PDT and Adaptive Immunity Recognizing Specific Antigens
	21.5	 Cancer and Immunosuppression
		21.5.1	 Regulatory T-Cells
		21.5.2	 Myeloid Suppressor Cells
		21.5.3	 Immature Dendritic Cells
		21.5.4	 Indoleamine 2,3-Dioxygenase
	21.6	 PDT and Immunostimulant Combinations
	21.7	 PDT and Checkpoint Inhibitors
	21.8	 Concluding Remarks and Clinical Applications
	References
22: Reprogramming of Tumor Microenvironment in Therapy
	22.1	 Introduction
	22.2	 Recruitment of Inflammatory Cells by Cancer Cells
	22.3	 The Role of TAM Macrophages in the Tumor Microenvironment
	22.4	 Polarization of the Microenvironmental Cell Phenotype
	22.5	 Reversion of Tumor Microenvironment
	22.6	 Instead of Conclusion
	References
23: Immunotherapies Targeting a Tumor-Associated Antigen 5T4 Oncofetal Glycoprotein
	23.1	 Introduction
		23.1.1	 5T4 Trophoblast Glycoprotein Is an Oncofetal Antigen
	23.2	 5T4 and Epithelial Mesenchymal Transition (EMT)
	23.3	 5T4 Modulation of Chemokine and Wnt Signaling Pathways
	23.4	 Vaccines
		23.4.1	 Preclinical Studies
		23.4.2	 Early-Phase Clinical Trials of MVA-h5T4 (TroVax)
		23.4.3	 TroVax Phase III Clinical Trial in RCC
		23.4.4	 Insights from the 5T4 KO Mouse
		23.4.5	 Improving Vaccine Regimens
	23.5	 5T4 Antibody-Targeted Superantigen Therapy
		23.5.1	 Preclinical Studies
		23.5.2	 Early-Phase Clinical Studies
		23.5.3	 A Phase II/III Clinical Trial in RCC
	23.6	 Other 5T4 Antibody-Targeted Therapies
		23.6.1	 Antibody-Drug Conjugates (ADC)
		23.6.2	 Direct 5T4 Antibody Effects
		23.6.3	 5T4 Chimeric Antigen Receptors
	23.7	 Concluding Remarks
	References
24: Aging and Cancer Prognosis
	24.1	 Introduction
	24.2	 Aging and Cancer Demography
	24.3	 General Content of Cellular Aging
	24.4	 Clinical Aspects of Aging, Age-Related Disease, and Immunity
	24.5	 Hypothesis of Increase in Cancer Risk by Aging
	24.6	 An Epitome of Aging, Immunity, and Cancer
	24.7	 Aging and Immunity as Prognostic Factors in Cancer
	24.8	 Cancer Treatment Approaches Based on Aging and Immunity
	24.9	 Conclusion
	References
25: Biomarkers for Immune Checkpoint Inhibitors
	25.1	 Introduction
	25.2	 Overview of Immune Checkpoint Inhibitors: Mechanism of Action
		25.2.1	 Central Tolerance
		25.2.2	 Peripheral Tolerance
		25.2.3	 CTLA-4 Receptor
		25.2.4	 PD-1 Receptor
		25.2.5	 Immune Escape Mechanism
	25.3	 The Essential Need for Biomarkers
	25.4	 Demographic Characteristics
		25.4.1	 Sex
		25.4.2	 Age
		25.4.3	 Tumor Size
	25.5	 PD-L1 Expression
	25.6	 Tumor-Infiltrating Lymphocytes (TIL)
	25.7	 TIL Molecular Characteristics
	25.8	 Tumor Mutational Burden
	25.9	 Mutations in the Specific Genes
	25.10	 Heterogeneity in the HLA Genes and Expression of MHC
	25.11	 Expression of Immune-Related Genes
	25.12	 Blood Biomarkers
		25.12.1 Lactate Dehydrogenase
		25.12.2 Peripheral Cell Count
		25.12.3 Other Blood Biomarkers
	25.13	 The Importance of Gut Microbiota
	25.14	 Other Possible Biomarkers
	25.15	 Combination of Different Biomarkers
	25.16	 Conclusion
	References
26: Cancer Nanomedicine: Special Focus on Cancer Immunotherapy
	26.1	 Introduction
	26.2	 Overview of the Immune System and Cancer
		26.2.1	 Immune Cells and Mediators in Tumors
		26.2.2	 Tumor Immune Surveillance and Cancer Immunoediting
		26.2.3	 Tumor Immune Evasion
		26.2.4	 Current Immunotherapies
		26.2.5	 Cancer Vaccines
		26.2.6	 Adoptive Cell Therapy (ACT)
		26.2.7	 Checkpoint Inhibition
		26.2.8	 Cytokine Therapy
		26.2.9	 Monoclonal Antibody
		26.2.10 Oncolytic Virus Immunotherapy
	26.3	 Application of Nanotechnology in Cancer
		26.3.1	 Nanodiagnostics
		26.3.2	 Nanomaterials in Medical Imaging
			26.3.2.1	 Nanotechnology in Traditional Imaging
				General Principles
					Nanoparticle-Mediated Targeting in Traditional Imaging
					Nanotechnology in MRI
	26.4	 Nanotechnology in Other Imaging Systems
		26.4.1	 Nanotechnology in Molecular Imaging
			26.4.1.1	 Biosensors and Role of Nanotechnology in Their Developments
		26.4.2	 Nanotherapy and Nanotoxicity
	26.5	 Nanotechnology Against Tumors
		26.5.1	 Aims and Mechanisms of Action
		26.5.2	 Nanoparticle’s Characteristics
		26.5.3	 Optical Properties of Nanoparticles
		26.5.4	 Physical Properties of Nanoparticles
			26.5.4.1	 Chemical Characteristics of Nanoparticles
			26.5.4.2	 Metallic and Metal Oxide
			26.5.4.3	 Quantum Dots
			26.5.4.4	 Carbon Nanoparticle
			26.5.4.5	 Polymeric Nanoparticles
		26.5.5	 Challenges and Opportunities
		26.5.6	 Nanoparticle’s Interaction with Cancer Cells
		26.5.7	 Antiangiogenesis
		26.5.8	 Silver NPs (AgNPs)
		26.5.9	 Chitosan NPs (CNPs)
		26.5.10 Silica NPs (SiNPs)
		26.5.11 Selenium NPs (SeNPs)
		26.5.12 Tetrac NPs
	26.6	 Nanocarriers
		26.6.1	 Nanocarriers in Cancer
		26.6.2	 Nanocarriers in Cancer Treatment
		26.6.3	 Combinatorial Strategy in Cancer Treatment Using Nanocarriers
		26.6.4	 Nanocarriers with FDA Approval for Cancer Treatment
	26.7	 Nanoparticle-Based Immunotherapy for Cancer
	26.8	 Concluding Remarks
	References
27: Oncolytic Viruses as Immunotherapeutic Agents
	27.1	 Introduction
	27.2	 Model of Oncolytic Virus and Macroorganism Interaction
	27.3	 Interaction Between Oncolytic Virus and Tumor
		27.3.1	 Model of Tumor Destruction Under the Virus Influence
		27.3.2	 Immunogenic Cell Death
	27.4	 Oncolytic Viruses of Current Interest
		27.4.1	 Artificially Modified Viruses
			27.4.1.1	 Oncolytic Herpesviruses
			27.4.1.2	 Oncolytic Adenoviruses
			27.4.1.3	 H101
			27.4.1.4	 The Immune Response to Adenoviruses
		27.4.2	 Naturally Occurring Oncolytic Viruses
			27.4.2.1	 Newcastle Disease Virus
			27.4.2.2	 Reovirus
	27.5	 Combined Immunotherapy
	27.6	 Conclusion
	References
28: Immune Targeting of Oncogenic HPV as Therapy for Cancer
	28.1	 Introduction
	28.2	 The Burden of HPV-Associated Cancers
	28.3	 The HPV Infection Life Cycle
	28.4	 HPV Carcinogenesis: Immune Deviation and Persistent HPV Infection
	28.5	 Therapeutic Vaccine Strategies
		28.5.1	 Protein/Peptide Vaccines
		28.5.2	 Listeria-Based Vaccines
		28.5.3	 Vaccinia-Based Vaccines
		28.5.4	 RNA Virus-Based Vaccines
		28.5.5	 Nucleic Acid-Based Vaccines
		28.5.6	 Cell-Based Vaccines
	28.6	 Adoptive Cell Transfer (ACT)
	28.7	 Optimizing Immune Intervention Strategies
		28.7.1	 Early Cancers
		28.7.2	 Later-Stage Cancers
	28.8	 Concluding Remarks
	References
29: New Advances in Radioimmunotherapy for the Treatment of Cancers
	29.1	 Introduction
	29.2	 Principles of Radioimmunotherapy
	29.3	 Radionuclides and Radiolabelling Techniques for Therapy
		29.3.1	 Radionuclides
		29.3.2	 Labelling Techniques
	29.4	 Treatment of B-Cell Lymphoma with Anti-CD20 Antibodies
	29.5	 Promising Results for Hemopathies Using Other Antibodies
		29.5.1	 Targeting of Lymphoma with Anti-CD22 Antibodies
		29.5.2	 Targeting of Multiple Myeloma Using Anti-CD138 Antibodies
	29.6	 RIT of Metastatic Prostate Cancer
	29.7	 RIT with Alpha-Emitting Radionuclides
		29.7.1	 Therapeutic Indications
		29.7.2	 Limited Availability
		29.7.3	 Issues and Current Developments
	29.8	 High Efficacy of Pretargeting Approaches
		29.8.1	 Metastatic Thyroid Carcinoma
		29.8.2	 Other Neoplasias
	29.9	 Immuno-PET: The Future for Dosimetry Assessment and Patient Selection
		29.9.1	 Immuno-PET and Development of New Drugs
		29.9.2	 Patient Selection for Therapy
		29.9.3	 Determination of the Cumulated Activity Concentration for RIT
		29.9.4	 Therapy Response
	29.10	 Conclusion
	References
30: Radiation and Immunity: Hand in Hand from Tumorigenesis to Therapeutic Targets
	30.1	 Introduction
	30.2	 Radiation and Cancer
		30.2.1	 Space Radiation
		30.2.2	 Radiation Therapy
		30.2.3	 Computed Tomography (CT) Radiation
		30.2.4	 High-Frequency (Radio Frequency and Microwave) Electromagnetic Radiation
		30.2.5	 Low-Dose Nuclear Radiation
		30.2.6	 Solar UV-B Radiation (280–320 nm)
	30.3	 Radiation, Immunity, and Cancer: Cellular Pathways
		30.3.1	 When Radiation and Immunity Go Hand in Hand to Subvert
		30.3.2	 When Radiotherapy and Immunotherapy Work Hand in Hand to Treat
	30.4	 Radiation, Immunity, and Cancer: Clinical Implications
		30.4.1	 Curative Purposes
			30.4.1.1	 Radiotherapies
			30.4.1.2	 Radionuclide-Bearing Monoclonal Antibody Therapies
		30.4.2	 Prognostic Purposes
		30.4.3	 Complications and Cautions
			30.4.3.1	 Adverse Events
			30.4.3.2	 Mortality
			30.4.3.3	 Immunodeficiency
		30.4.4	 Emerging Modern Radiotherapy Protocols
	References
31: Hurdles in Cancer Immunotherapy
	31.1	 General Hurdles
		31.1.1	 Limitations of Current Animal Models in Predicting Efficacy of Cancer Immunotherapy Modalities in Human Body
		31.1.2	 Complexity of Concepts and Mechanisms Pertaining to Cancer, Tumor Heterogeneity, and Immune Escape
		31.1.3	 Lack of Specific Clinical Efficacy Biomarker(s) for Assessment of Cancer Immunotherapies
		31.1.4	 Conventional Clinical Criteria Do Not Delineate Different Response Patterns to Cytotoxic Agents and Immunotherapies
		31.1.5	 Obtaining Approval to Initiate Clinical Trials Is Time-Consuming
		31.1.6	 Challenges in Design of Clinical Trials
		31.1.7	 Reagents for Combination Immunotherapy Studies Are Limited
		31.1.8	 Limitation of Funding to Support Knowledge Translation
		31.1.9	 Limited Number of Groups with Both Scientists and Clinicians Aiming at Translation Research
		31.1.10 Insufficient Circulation and Exchange of Evidence Needed to Advance the Field
	31.2	 Chimeric Antigen Receptor (CAR) T-Cell Immunotherapy
		31.2.1	 Hurdles Related to Mechanism and Process of Research
			31.2.1.1	 Limited Infrastructure for Efficient Knowledge Translation
			31.2.1.2	 Need to Release Certificate Prior to Clinical Evaluation of CAR T Cells as Genetically Modified Organisms
			31.2.1.3	 Difference in Requirements Among Various Settings
			31.2.1.4	 Lack of Standard and Specific Guidance
			31.2.1.5	 High Burden of Documentation Needed Even in Early Phase of Application for Clinical Trials
			31.2.1.6	 Product Chain Identity
			31.2.1.7	 Lack of Specific Regulatory Requirements for CAR T Cells to Facilitate Knowledge Translation
		31.2.2	 Practical Hurdles
			31.2.2.1	 Labor-Intensive Nature of Adoptive Cell Transfer (ACT)
			31.2.2.2	 Limited Number of Cancers with Natural Tumor-Reactive Lymphocytes Eligible for Isolation and Expansion
			31.2.2.3	 Dependence on the In Vivo Maintenance of T-Cell Populations
		31.2.3	 Some Other Pending Issues
			31.2.3.1	 Determination of Ideal CAR T-Cell Population Subset, Phenotype, and Construct
			31.2.3.2	 Selecting Appropriate Animal Models to Investigate the Safety and Efficacy of CAR T-Cell Products
			31.2.3.3	 Feasible and Cost-Efficient Production Process
			31.2.3.4	 Determining the Dose of CAR T Cells
	31.3	 Immunological Hurdles Restricting the Efficiency of Antitumor Cytolytic T Cells
		31.3.1	 Self-Nature of Most Tumor Antigens
		31.3.2	 Low Levels of Costimulation
		31.3.3	 Immune Regulatory Cells
			31.3.3.1	 Immunosuppression Activity of CD4+ Suppressor Cells
			31.3.3.2	 Immunosuppression Activity of CD8+ Suppressor Cells
			31.3.3.3	 Immunosuppression Activity of Myeloid-Derived Suppressor Cells
			31.3.3.4	 IL-13 Secreting Natural Killer T (NKT) Cells
		31.3.4	 T-Cell Allergic Through Induction of Indoleamine 2,3-Dioxygenase
		31.3.5	 Exhaustion of T-Cells
			31.3.5.1	 Inhibitory Checkpoints Associated with T-Cell Exhaustion
		31.3.6	 Mechanisms of Tumor Evasion in Late Stages of Tumor Development
	31.4	 Immunoediting
	31.5	 Tumor Resistance
		31.5.1	 Defective Death Receptor Expression or Signaling
		31.5.2	 Resistance to Perforin and the Granzyme B Pathway
		31.5.3	 Genetic Instability as a Consequence of Malignant Transformation
		31.5.4	 Resistance to Apoptosis by Loss of Proapoptotic Regulator
			31.5.4.1	 P53 Expression
			31.5.4.2	 Phosphatase and Tensin Homology Expression
			31.5.4.3	 Wnt-β-Catenin Pathway
		31.5.5	 Dual Role of CTLs: Attacking Tumor Cells and Selection of Resistant Variants
		31.5.6	 Actin Cytoskeleton
		31.5.7	 Events in Antigen Processing
			31.5.7.1	 Impaired Proteasomal Mechanisms
			31.5.7.2	 Deranged Intracellular Peptide Transport
			31.5.7.3	 Loss of β2-Microglobulin Protein Function
		31.5.8	 Safety Concerns
		31.5.9	 Toxicities Related to CAR T-Cell Therapy
		31.5.10 Toxicities Related to Immune Checkpoint Inhibitors
			31.5.10.1	 Ipilimumab
			31.5.10.2	 Nivolumab
			31.5.10.3	 Pembrolizumab
		31.5.11 Toxicities Related to TCR-Modified T-Cell Therapy
	31.6	 Hurdles of CAR T-Cell Cancer Immunotherapy in Solid Tumors
		31.6.1	 T-Cell Trafficking
		31.6.2	 T-Cell Infiltration
		31.6.3	 Immunosuppressive Microenvironment
			31.6.3.1	 Inhibitory Cytokines
			31.6.3.2	 Inhibitory Immuno-Checkpoints
			31.6.3.3	 Immune Suppressor Cells
		31.6.4	 Toxicity
	31.7	 Other Topics
		31.7.1	 Challenges in Antigen Selection
		31.7.2	 Hurdles Against Bispecific Antibodies
			31.7.2.1	 The Issues of Stability
		31.7.3	 Need for New Interventions to Enhance Efficacy of Current Immunotherapies in Non-T-Cell-Inflamed Phenotype
	31.8	 Solid Tissue Cancer-Specific Hurdles
		31.8.1	 Melanoma
		31.8.2	 Pancreas
		31.8.3	 Head and Neck Cancers
	References
32: Ethical Considerations in Cancer Immunotherapy
	32.1	 Introduction
	32.2	 Ethical Issues in Immunotherapy of Cancer
	32.3	 Unique Toxicities
	32.4	 Evaluation of Efficacy in the Clinical Trial and Non-research Settings
	32.5	 Ethical Justification for Initiation of Treatment in Individual Patients
	32.6	 Concluding Remarks
	References
Index