Immunotherapy Against Lung Cancer: Emerging Opportunities and Challenges

Preface
Acknowledgments
Contents
About the Editors
1: Introduction to Lung Cancer
	1.1	 Introduction
	1.2	 Etiology of Lung Cancer
	1.3	 Epidemiology of Lung Cancer
	1.4	 Classification of Lung Cancer
	1.5	 Pathophysiology of Lung Cancer
	1.6	 Diagnosis
	1.7	 Treatment Strategies
	1.8	 Conclusion
	References
2: Immunobiology of Lung Cancer
	2.1	 Introduction
	2.2	 Innate and Adaptive Immune System Regulation of Cancer
	2.3	 Molecular Mechanism of Cancer
	2.4	 Lung Cancer
	2.5	 Genetic Epidemiology
	2.6	 Tobacco as a Prominent Cause of Lung Cancer
	2.7	 Major Health Effects of Smoking
	2.8	 Immune Escape Mechanism in Lung Cancer
	2.9	 Immune Response to Lung Cancer
	2.10	 Future Perspectives
	2.11	 Conclusion
	References
3: Evolution of Lung Cancer Treatment from Classical Chemotherapy to Advanced Immunotherapy
	3.1	 Introduction
	3.2	 Conventional Lung Cancer Treatments
		3.2.1	 Chemotherapy
			3.2.1.1	 Chemotherapy in Lung Cancer
		3.2.2	 Radiation Therapy
			3.2.2.1	 Radiation Therapy in Lung Cancer
		3.2.3	 Surgery
			3.2.3.1	 Role of Surgery in Lung Cancer Treatment
	3.3	 Chemotherapy
		3.3.1	 Origin
		3.3.2	 Mechanism of Action
			3.3.2.1	 Alkylating Agents
			3.3.2.2	 DNA Topoisomerase Inhibitors
		3.3.3	 Resistance to Chemotherapy
			3.3.3.1	 Small-Cell Lung Cancer
			3.3.3.2	 Non-Small-Cell Lung Cancer (NSCLC)
		3.3.4	 Side Effects
	3.4	 Immunotherapy
		3.4.1	 Origin
		3.4.2	 Mechanism of Action
		3.4.3	 Clinical Trials
		3.4.4	 Efficacy of Immunotherapy for Lung Cancer
	3.5	 Road Map from Chemotherapy to Immunotherapy
		3.5.1	 Anti-Angiogenic Therapy
		3.5.2	 Targeted Therapy
			3.5.2.1	 Target as Epidermal Growth Factor Receptor (EGFR)/ERBB/HER
			3.5.2.2	 Target as Anaplastic Lymphoma Kinase (ALK)
			3.5.2.3	 Other Common Drug Targets
	3.6	 Combination Therapy
		3.6.1	 Chemotherapy with Immunotherapy
		3.6.2	 Immunotherapy with Radiation Therapy
		3.6.3	 Chemotherapy with Radiation Therapy
	3.7	 Conclusion
	References
4: Revolutionizing Lung Cancer Treatment: Recent Breakthroughs in Immunotherapy
	4.1	 Introduction to Lung Cancer
	4.2	 Recent Breakthroughs in Immunotherapy for NSCLC
		4.2.1	 Developments in Perioperative Immunotherapy
		4.2.2	 Research on Circulating Tumour DNA (ctDNA) as Effective Biomarkers
		4.2.3	 Approaches in Adjuvant Immunotherapy
		4.2.4	 The Concept of Neoadjuvant Immunotherapy
		4.2.5	 Immunotherapy for Advanced NSCLC
		4.2.6	 Combined Immunotherapy and Chemotherapy
			4.2.6.1	 Combined Immunization with JAK Inhibitors
			4.2.6.2	 Immunization Combined with Poly ADP-Ribose Polymerase (PARP) Inhibitors
		4.2.7	 Immune Combination Antibody–Drug Conjugate (ADC)
		4.2.8	 Anti PD-1 and PD-L1 Inhibitors in NSCLC
		4.2.9	 Novel Immune Checkpoint Inhibitor Under Investigation in In Advanced Non-Small-Cell Lung Cancer (NSCLC) Treatment
	4.3	 Recent Breakthroughs in Immunotherapy for SCLC
	4.4	 Lung Cancer Targeted Therapy and Traditional Chemotherapy
	4.5	 Combined Immunotherapy and Chemotherapy
	4.6	 Theranostic in Lung Cancer
	4.7	 Neoepitopes as Therapeutic Targets for Lung Cancer
	4.8	 Revolutionizing Approaches in Lung Cancer Vaccines
		4.8.1	 Prophylactic Vaccines
		4.8.2	 Therapeutic Vaccines
	4.9	 Synergistic Combinations and Innovative Approaches
		4.9.1	 Checkpoint Inhibitor as First-Line Treatment for SCLC
		4.9.2	 Other Immunomodulatory and Agonistic Molecules
	4.10	 Conclusion
	References
5: PD-1/PD-L1 Inhibitors for the Treatment of Lung Cancer
	5.1	 Introduction
	5.2	 Overview of Immune Checkpoint Signaling
	5.3	 First-Generation Immune Checkpoint Blockade (CTLA4 Intervention)
	5.4	 PD-1/PD-L1-Driven Immune Checkpoint Inhibition
		5.4.1	 PD-1 Therapeutic Antibodies
		5.4.2	 PD-L1 Antibodies
	5.5	 ICI Combination Therapy
	5.6	 Current Perspective and Path Forward
	References
6: CTLA-4 Inhibitors for the Treatment of Lung Cancer
	6.1	 Introduction
	6.2	 Association Between Lung Cancer and the Immune System
	6.3	 Immune Checkpoints in Lung Cancer
	6.4	 CTLA-4 and Their Ligands in Cancer
	6.5	 Mechanism and Functions of CTLA 4 Pathway in Cancer
	6.6	 Anti-CTLA-4 Agents in Anticancer Therapy
	6.7	 Ipilimumab
	6.8	 Tremelimumab
	6.9	 Efficacy and Mode of Action of CTLA-4 Inhibitors
	6.10	 Biomarkers of CTLA-4 Inhibitor Treatment Efficacy
	6.11	 Adverse Events Associated with CTLA-4 Therapy
	6.12	 Limitations of CTLA-4 Inhibitors
	6.13	 Conclusion
	References
7: Adoptive T-Cell Therapy for the Treatment of Lung Cancer
	7.1	 Introduction
	7.2	 Cancer Immunology
	7.3	 Epidemiological Incidences of Lung cancer
	7.4	 Signaling Molecules of Lung Cancer
	7.5	 Epidermal Growth Factor Receptor (EGFR)
	7.6	 Vascular Endothelial Growth Factor (VEGF)
	7.7	 Mitogen-Activated Protein Kinase Phosphatase 1 (MKP-1)
	7.8	 Peroxisome Proliferator-Activated Receptor
	7.9	 Treatment Strategies
	7.10	 Lung Cancer Vaccines
	7.11	 Tumor-Infiltrating Lymphocyte [TIL] Therapy
	7.12	 Chimeric Antigen Receptor T-Cell [CAR-T] Therapy in Lung Cancer
	7.13	 Tackling of T-Cell Therapy–Related Consequences
	7.14	 Tackling the Challenges in ACT
	7.15	 Trends, Challenges, and Future Directions of T-Cell Therapy
	7.16	 Trends in T-Cell Therapy
		7.16.1	 CAR-T Cell Therapy
		7.16.2	 Personalized T-Cell Therapy
		7.16.3	 Combination Therapies
		7.16.4	 Solid Tumors
		7.16.5	 Off-the-Shelf T-Cell Therapy
	7.17	 Challenges
		7.17.1	 CAR-T Cell Therapy
		7.17.2	 Personalized T-Cell Therapy
		7.17.3	 Combination Therapies
		7.17.4	 Solid Tumors
		7.17.5	 Off-the-Shelf T-Cell Therapy
	7.18	 Future Directions
		7.18.1	 CAR-T Cell Therapy
		7.18.2	 Personalized T-Cell Therapy
		7.18.3	 Combination Therapies
		7.18.4	 Solid Tumors
		7.18.5	 Off-the-Shelf T-Cell Therapy
	7.19	 Conclusion
	References
8: LAG-3 Inhibitors for the Treatment of Lung Cancer
	8.1	 Introduction
	8.2	 Structure and Functions of LAG-3
		8.2.1	 Expression of LAG-3
		8.2.2	 The LAG3 Signaling
		8.2.3	 Immunological Functions of LAG 3
		8.2.4	 Roles of LAG-3 Inhibitors in Tumors
	8.3	 Anti-LAG-3 Antibody-Based Therapies
	8.4	 Anti-LAG-3 Cell-Based Therapies
	8.5	 LAG-3 Clinical Trials with Experimental Medicine
	8.6	 Therapies for LAG-3 Inhibition
		8.6.1	 Anti-LAG-3 Monoclonal Antibodies
			8.6.1.1	 Relatlimab (BMS-986016)
			8.6.1.2	 Nivolumab
			8.6.1.3	 Ipilimumab
			8.6.1.4	 Pembrolizumab (MK-3475)
		8.6.2	 Anti-LAG-3 Bispecific
			8.6.2.1	 Tebotelimab (Formerly MGD013)
			8.6.2.2	 RO7247669
		8.6.3	 Soluble LAG-3–Ig Fusion Proteins: Eftilagimod Alpha
	8.7	 LAG3 Inhibition and Evaluation of Targeting Agents in Lung Cancer Trials
	8.8	 Conclusion
	References
9: IDO and TGF-β Inhibitors for the Treatment of Lung Cancer
	9.1	 IDO Inhibitors
		9.1.1	 Introduction
		9.1.2	 IDO and Proliferation of Cancer Cells
		9.1.3	 Structure of Active Site of IDO Enzyme
		9.1.4	 Pharmacophore of IDO Inhibitors
		9.1.5	 Classification of IDO Inhibitors
		9.1.6	 Well-Known IDO Inhibitors
			9.1.6.1	 Epacadostat
			9.1.6.2	 Navoximod (NLG919, GDC-0919)
			9.1.6.3	 Linrodostat (BMS-986205)
			9.1.6.4	 PF-06840003 (Synonyms EOS200271)
			9.1.6.5	 Indoximod (1-Methyl-D-Tryptophan, 1-MT, NLG-8189)
			9.1.6.6	 4-Phenylimidazole (4-PI, PIM, 4PI)
		9.1.7	 Natural IDO Inhibitors
		9.1.8	 IDO Inhibitors for Lung Cancer
	9.2	 Transforming Growth Factor-β Inhibitors
		9.2.1	 Introduction
		9.2.2	 Different Targets of TGF-β Signaling Pathway
			9.2.2.1	 In the Ligand Level
			9.2.2.2	 Ligand Traps and Neutralizing Antibodies
			9.2.2.3	 Combined Vaccine/Antisense
			9.2.2.4	 Peptide Aptamers
			9.2.2.5	 TGF-β Receptor Kinase Inhibitors
		9.2.3	 Most Widely Studied TGF-β Receptor Kinase Inhibitors
			9.2.3.1	 Vactosertib
			9.2.3.2	 Sb-431542
			9.2.3.3	 Sb-505124
			9.2.3.4	 Sb-525334
			9.2.3.5	 TP0427736
			9.2.3.6	 IN-1130 (In2Gen)
			9.2.3.7	 Galunisertib
			9.2.3.8	 LY3200882
			9.2.3.9	 LY364937
			9.2.3.10	 RepSox
			9.2.3.11	 LY2109761
			9.2.3.12	 R-268712
			9.2.3.13	 A-77-01
			9.2.3.14	 A-83-01
			9.2.3.15	 GW 788388
			9.2.3.16	 Sb-208
		9.2.4	 Natural Products with TGF-β Receptor I Antagonistic/Inhibitor Properties
		9.2.5	 Structure of TβRI and Pharmacophoric Elements of TGF-β1 Receptor Inhibitors
		9.2.6	 New TGF-β Receptor I Inhibitors for Treating Lung Cancer
	9.3	 Conclusions
	References
10: OX40 and CD40 Agonists for the Treatment of Lung Cancer
	10.1	 Introduction
		10.1.1	 Tumor Microenvironment in Lung Cancer
	10.2	 Development of Immunotherapy for Lung Cancer
		10.2.1	 Non-small-Cell Lung Cancer Stem Cells
	10.3	 Molecular-Based Targeted Therapies for Lung Cancer
		10.3.1	 OX40
			10.3.1.1	 Targeting of OX40 in Lung Cancer
			10.3.1.2	 OX40 Agonist Development
			10.3.1.3	 Drugs Targeting OX40 and OX40L in Lung Cancers
		10.3.2	 CD40
			10.3.2.1	 Biological Relevance of CD40/CD40L
			10.3.2.2	 Implications for the Development of CD40 Agonists
			10.3.2.3	 Bispecific Approaches Targeting CD40
			10.3.2.4	 Combination Treatment with Other Therapies
	10.4	 Other Potential Targets
		10.4.1	 IDO
		10.4.2	 TLR
		10.4.3	 Arginase Inhibitors
		10.4.4	 Oncolytic Peptides
	10.5	 Conclusions
	References
11: Exploring the Therapeutic Potential of ICOS and GITR Agonists in Lung Cancer
	11.1	 Introduction and Epidemiology
	11.2	 Promise of Immunotherapy for Lung Cancer
	11.3	 Inducible T-Cell Co-Stimulatory (ICOS)
	11.4	 Targeting ICOS for Immunotherapy
	11.5	 Glucocorticoid-Induced TNFR-Related Protein (GTIR) Agonists
	11.6	 Conclusion and Future Prospects
	References
12: Vaccines and Oncolytic Virus for the Treatment of Lung Cancer
	12.1	 Introduction
		12.1.1	 Current Lung Cancer Therapy
	12.2	 Vaccines for Lung Cancer
		12.2.1	 Mechanism of Action of Lung Cancer Vaccines
	12.3	 Clinical Studies with Vaccines for the Treatment of Lung Cancer
	12.4	 Development of Therapeutic Vaccines for Lung Cancer: Challenges and Limitations
	12.5	 Oncolytic Virus for Lung Cancer Therapy
		12.5.1	 Anticancer Mechanism of Oncolytic Virus
		12.5.2	 Vaccinia Virus
		12.5.3	 Coxsackievirus
		12.5.4	 Adenovirus
		12.5.5	 Seneca Valley Virus
		12.5.6	 Reovirus
	12.6	 Combination Therapeutic Strategy for Lung Cancer
		12.6.1	 Combination of Oncolytic Virus with Conventional Therapy
		12.6.2	 Combination of Oncolytic Virus with Immunotherapy
		12.6.3	 Other Novel Combinations of Oncolytic Virus
	12.7	 Delivery of Oncolytic Virus
	12.8	 Preclinical and Clinical Studies with Oncolytic Virus for the Treatment of Lung Cancer
	12.9	 Development of Oncolytic Virus for Lung Cancer: Challenges and Limitations
	12.10	 Conclusion
	References
13: Targeting Toll-Like Receptors for the Treatment of Lung Cancer
	13.1	 Introduct.ion
	13.2	 Function of Toll-Like Receptor in Lung Cancer
	13.3	 Toll-Like Receptors and Their Ligands
		13.3.1	 Toll-Like Receptor 2 (TLR2)
		13.3.2	 Toll-Like Receptor 3 (TLR3)
		13.3.3	 Toll-Like Receptor 4 (TLR4)
		13.3.4	 Toll-Like Receptor 5 (TLR5)
		13.3.5	 Toll-Like Receptor 6 (TLR6)
		13.3.6	 Toll-Like Receptor 7 (TLR7)
		13.3.7	 Toll-Like Receptor 8 (TLR8)
		13.3.8	 Toll-Like Receptor 9 (TLR9)
	13.4	 Conclusion
	References
14: Current and Future Perspectives of Combining Chemotherapy and Stereotactic Body Radiation Therapy with Immunotherapy in the Treatment of Lung Cancer
	14.1	 Introduction
	14.2	 Lung Cancer Treatment Modality
		14.2.1	 Role of Surgery in Lung Cancer
		14.2.2	 Chemotherapy for Lung Cancer
		14.2.3	 Immunotherapy for Lung Cancer
		14.2.4	 Radiation Therapy for Lung Cancer
	14.3	 Limitations of Conventional RT in Lung Cancers
	14.4	 SBRT and Its Use in Lung Cancer
	14.5	 Combination Therapy: Rationale and Evidence
		14.5.1	 SBRT + Immunotherapy
		14.5.2	 Immunotherapy and SBRT Trials
		14.5.3	 Chemotherapy + Immunotherapy
		14.5.4	 Immunotherapy + Chemotherapy Trials
	14.6	 Safety
	14.7	 Future Directions
	References
15: Lung Cancer Therapy: Synergistic Potential of PD-1/PD-L1 and CTLA-4 Inhibitors
	15.1	 Introduction
	15.2	 T-Cell Activation Pathways
		15.2.1	 CTLA-4 Pathway
		15.2.2	 PD-L1 Pathway
	15.3	 T-Cell Receptors
		15.3.1	 Cytotoxic T-Lymphocyte-Associated Antigen-4
			15.3.1.1	 Cancer and Cytotoxic CTLA-4
			15.3.1.2	 Anti-CTLA-4 Agents in Anticancer Therapy
				15.3.1.2.1 Ipilimumab
				15.3.1.2.2 Tremelimumab
				15.3.1.2.3 Durvalumab and Tremelimumab
				15.3.1.2.4 Nivolumab and Ipilimumab
				15.3.1.2.5 Nivolumab Plus Ipilimumab
	15.4	 PD-L1 Inhibitors
		15.4.1	 Enhancement of T-Cell Activity
		15.4.2	 Induction of T-Cell Proliferation
		15.4.3	 Promotion of Cytokine Secretion
		15.4.4	 Modulation of Tumor Microenvironment
	15.5	 Synergistically Combinational Approach of CTLA-4 and PD-1 Pathway Inhibitors in Cancer
	15.6	 Conclusion
	References
16: Synergistic Potential of Antigen-Specific Vaccines and Immunomodulatory Agents for Lung Cancer Treatment
	16.1	 Introduction
	16.2	 Cancer Vaccine
		16.2.1	 Whole Tumor Cell Vaccine
		16.2.2	 Tumor-Specific Antigen Vaccine
		16.2.3	 Host Immune Response
		16.2.4	 Pros and Cons of Cancer Vaccines
	16.3	 Immune Modulators
		16.3.1	 Role in Lung Cancer
		16.3.2	 Immune Checkpoint Molecules
		16.3.3	 Monoclonal Antibody
		16.3.4	 Emerging Immune Checkpoint Inhibitors: Novel Target for the Treatment of NSCLC
		16.3.5	 Integrating Chemotherapy with Immune Checkpoint Inhibitors
		16.3.6	 Modulating T-Cell Response with Immunomodulatory Agents
		16.3.7	 Synergistic Adjuvants
	16.4	 Conclusion
	References
17: Important Biomarkers for Better Evaluation of Checkpoint Inhibitors and Other Immunotherapies in Lung Cancer
	17.1	 Expression of PD-L1
	17.2	 TMB (Tumour Mutational Burden)
	17.3	 TILs (Tumour-Infiltrating Lymphocytes)
	17.4	 Specific Genotypes for Tumours
	17.5	 Biomarkers of Gene Expression
	17.6	 Serological Biomarkers
	17.7	 Biomarkers in Peripheral Blood
		17.7.1	 NLR (Neutrophil-to-Lymphocyte Ratio)
		17.7.2	 Lactate Dehydrogenase
		17.7.3	 Immunological Cells in the Peripheral Region
		17.7.4	 ctDNA (Circulating Tumour DNA)
		17.7.5	 Soluble PD-L1
		17.7.6	 T-Cell Receptor (TCR) in Peripheral Blood
		17.7.7	 Peripheral Cytokines
	17.8	 Factors Relating to the Immune System
		17.8.1	 Beta-2-Microglobulin
		17.8.2	 B7-H4
		17.8.3	 TOX
		17.8.4	 Biomarkers for Hyper-progressive Illness
	17.9	 Conclusion
	References
18: Insight on the Clinical Trials of Immunotherapy for the Treatment of Lung Cancer
	18.1	 Introduction
		18.1.1	 Lung Cancer
		18.1.2	 Immunotherapy and Lung Cancer
		18.1.3	 Approved Therapeutics for Lung Cancer
	18.2	 Emerging Targets for Immunotherapeutics
		18.2.1	 CTLA-4
		18.2.2	 TIM-3
		18.2.3	 LAG-3
	18.3	 Immunostimulatory Molecules on T-Cells
		18.3.1	 OX40
		18.3.2	 ICOS
		18.3.3	 Other Immunostimulatory Molecules
	18.4	 Tumour Vaccines
	18.5	 Conclusion
	References
19: Future Perspectives of Cancer Immunotherapy for the Treatment of Lung Cancer
	19.1	 Brief Discussion of Evolution of Immunotherapy
	19.2	 Discovery of New Checkpoints for Exploration as Targets
	19.3	 Discussion of Immunotherapy Resistance and Novel Approaches for Its Management
		19.3.1	 Primary Resistance
		19.3.2	 Secondary Resistance
		19.3.3	 Novel Approaches for the Management of Resistance
	19.4	 Usage of Radiomics and Deep Learning
	19.5	 Other Potentials for Harnessing AI for Prediction of Clinical Outcomes
	19.6	 Role of Lung Microbiome
	19.7	 Discussion of Gut Microbiome and Implications with Respect to Lung Cancer Management
	19.8	 Discussion of Current Pitfalls and Future Scope
	References