Immunotherapy – A Novel Facet of Modern Therapeutics

Contents
About the Editors
1: Immunotherapy: A Concept
	1.1 History and Origin of Immunotherapy
	1.2 Theory of Immunotherapy
	1.3 Application of Immunotherapy in Various Diseases
		1.3.1 Immunotherapy for Cancer
		1.3.2 Immunotherapy for Autoimmune Diseases
		1.3.3 Immunotherapy for Allergy
		1.3.4 Immunotherapy for HIV Infection
		1.3.5 Immunotherapy for Hepatitis
		1.3.6 Immunotherapy for Neurodegenerative Diseases
	1.4 Conclusion
	References
2: Immunotherapy in Cancer: Immune Checkpoint Inhibitors; Changing Oncology Treatment Paradigm
	2.1 Introduction
	2.2 Preclinical Evidence of Immune Modulation
	2.3 Early Clinical Evidence of Immune Modulation
	2.4 PD-1 Another Important Immune Checkpoint Player
	2.5 Impressive Anti-Tumor Effect on PD-1 Blockade
	2.6 Predictive Biomarkers of Immune Response
	2.7 Resistance to Immune Checkpoint Inhibition
	2.8 Clinical Strategies to Overcome Resistance
	2.9 Future Path
	References
3: Vaccines as Immunotherapy
	3.1 Introduction
	3.2 Targets of Cancer Immunotherapy
		3.2.1 Tumor Associated Antigens (TAAs)
		3.2.2 Tumor Specific Antigens (TSAs)
		3.2.3 Oncoviral Antigens
	3.3 Cancer Immunotherapeutics
	3.4 Active Immunotherapy
		3.4.1 Vaccination
			Live Bacterial Vector Vaccine
			Live Viral Vector Vaccine
			Peptide-Based Vaccine
			Nucleic Acid Based Vaccine
	3.5 Prophylactic and Therapeutic Vaccines in Clinical Uses or in Clinical Trials for Cancers Caused by Viruses
		3.5.1 Cervical Cancer
		3.5.2 Hepatocellular Carcinoma (HCC)
		3.5.3 Burkit´s Lymphoma
		3.5.4 Kaposi´s Sarcoma
		3.5.5 Merkel Cell Carcinoma (MCC)
			Cytokine Therapy Against Cancer
			Immune Checkpoint Inhibitor Therapy
	3.6 Passive Immunotherapy
		3.6.1 Monoclonal Antibodies
		3.6.2 Small Molecule Inhibitors
			BCR-ABL as a Target
			VEGFR (Vascular Endothelial Growth Factor Receptor) as a Target
			EGFR and HER2 as a Target
			mTOR as a Target
		3.6.3 Chimeric Antigen Receptor (CAR) T-Cell Therapy
	3.7 Vaccine Against Cancers: Non-infectious targets
	3.8  Challenges and Future of Cancer Therapy
	3.9 Summary
	References
4: Immunotherapy for Autoimmune Diseases
	4.1 The Immune System: An Overview
	4.2 Autoimmunity and Immune Tolerance
	4.3 Autoimmune Diseases
	4.4 Immunotherapy for Autoimmune Diseases: General Considerations
	4.5 Checkpoint-Based Immunotherapy for Autoimmune Diseases
	4.6 Auto-Antigen Specific Immunotherapies for Autoimmune Diseases
	4.7 Anti-Cytokine (Anti-IL-1, Anti-IL-6, Anti-TNF Agents) Therapy for Autoimmune Diseases
	4.8 Anti-T-Cell Therapy for Autoimmune Diseases
	4.9 Anti-B-Cell Therapy for Autoimmune Diseases
	4.10 Current Immunotherapeutics in Clinical Trials for Autoimmune Diseases
	4.11 Financial Toxicity of Immunotherapies in Autoimmune Diseases
	4.12 Conclusion and Future Perspectives
	References
5: Immunotherapy in Neurodegenerative Disorders
	5.1 Introduction
	5.2 Neurodegenerative Diseases: Pathophysiology and Causes
	5.3 Milestones in the Treatment of Neurodegenerative Diseases
	5.4 Immunotherapy in Neurodegenerative Diseases
	5.5 Mechanisms of Immunotherapy
	5.6 Immunotherapy for AD: Active and Passive Immunizations
	5.7 Multiple Sclerosis: Pathology and Immunotherapy
	5.8 Off Label Use of Polyclonal Intravenous Immunoglobulin´s (Irving) for the Treatment of Remitting Multiple Sclerosis (RRMS)...
	5.9 Immunotherapy in PD: Alpha-Synuclein and Parkinson´s Disease
	5.10 Neuroinflammation and Glia Activation in Parkinson´s Disease
	5.11 Future Outlook: Different Immunotherpay Strategies Used to Treat Neurodegenerative Diseases
	References
6: Companion Diagnostics and Clinical Biomarkers for Immunotherapy
	6.1 Introduction
	6.2 Consensus on the Terminology and Definition of Term: Companion Diagnostics
	6.3 Parallel Road of Drug Development and CDx Development
	6.4 Clinical Trial Designs: Factors Considered in Designing the Protocol for Co-Development of CDx Assay and Drug
	6.5 Technologies Used for CDx Assay Development
	6.6 Impact of Companion Diagnostics
	6.7 Companion Diagnostic and Immunotherapy
	References
7: Novel Drug Delivery Systems for Immunotherapeutics
	7.1 Introduction
	7.2 Novel Drug Delivery Approaches
		7.2.1 Nanoparticles
		7.2.2 Liposomes
		7.2.3 Micelles
		7.2.4 Nanorods
		7.2.5 Hydrogels and Nanogels
	7.3 Conclusion
	References
8: Discovery, Screening Methods, Design Considerations, and Scale-up Aspects of Immunotherapeutic Drugs
	8.1 Introduction
		8.1.1 Development of Immunotherapeutic Vaccines
		8.1.2 Development of Checkpoint Inhibitors
		8.1.3 Development of Adaptive Cell Transfer Technology
			Ex Vivo Manipulation of NK Cells
			Pharmacological and Cellular Approaches
		8.1.4 Development of Immunotherapeutic Monoclonal Antibody Therapy and Tumor Agnostic Therapy
		8.1.5 Development of Oncolytic Viral Therapy
		8.1.6 Development of Non- Specific Immunotherapeutic Drugs
			Approaches for IVT mRNA
	8.2 Design Considerations and Scale-up Aspects of Immunotherapeutic Drugs
		8.2.1 Monoclonal Antibody Therapeutics
		8.2.2 Types of mAbs and Problems Associated with its Production
		8.2.3 Role of Mammalian Cell Lines
		8.2.4 Cellular Therapy
		8.2.5 Bioreactors for Cell Therapies
		8.2.6 Bioreactor Designs
		8.2.7 Automation Considerations for Cell Therapies
	8.3 Conclusion
	References
9: Pharmacokinetics, Pharmacodynamics, and Toxicology Aspects of Immunotherapeutics
	9.1 Introduction
	9.2 Pharmacokinetics of Immune Checkpoint Inhibitors (ICIs)
		9.2.1 Ipilimumab
		9.2.2 Nivolumab
		9.2.3 Pembrolizumab
		9.2.4 Atezolizumab
		9.2.5 Avelumab
		9.2.6 Durvalumab
	9.3 Pharmacodynamics of Immune Checkpoint Inhibitors
		9.3.1 Anti CTLA-4 Antibodies
		9.3.2 Anti PD-1 and PD-L1 Antibodies
			Nivolumab
			Pembrolizumab
			Atezolizumab
			Avelumab
			Durvalumab
	9.4 Combination with Chemotherapy or Other Immunotherapies: PD Considerations
	9.5 Significance of PD1 Expression in Tumors: Subgroup Analysis from Large Randomized Trials
	9.6 Immunotherapy and Toxicities
		9.6.1 CTLA-4 Inhibitors: Ipilimumab
		9.6.2 PD1/PDL1 Inhibitors: Nivolumab, Pembrolizumab
		9.6.3 Others: Atezolizumab (Tecentriq), Avelumab (Bavencio), Durvalumab (Imfinzi)
	9.7 Combination with Chemotherapy or Two Immunotherapies
	9.8 Predictors of Toxicity
	9.9 Dose Modifications
	9.10 Precautions and Warnings
	9.11 Treatment
	9.12 Conclusions
	References
10: Regulatory Affairs and Intellectual Property Rights in Immunotherapeutics
	10.1 Introduction
	10.2 Why Regulations
	10.3 Intellectual Property Rights Approaches
	10.4 Regulatory Requirements
		10.4.1 Regulatory Authorities Worldwide
			India
			Unites States
			United Kingdom
			Europe
			Australia
			Canada
		10.4.2 Non-Clinical Requirements in India
			Animal Pharmacology
			Animal Toxicology
				Systemic Toxicity Studies
		10.4.3 Clinical Development Approaches
		10.4.4 NDA Format: ICH
		10.4.5 New Drug Application (NDA) Format India
			Small Molecule
			Large Molecules
	10.5 Post-Approval Requirements
		10.5.1 Pharmacovigilance
		10.5.2 CMC Changes
	10.6 Conclusion
	References
11: Future Immunotherapy Challenges and Perspectives
	11.1 Introduction
	11.2 Approaches to Immunotherapy
		11.2.1 Biologics in Immunotherapy
		11.2.2 Small Molecules in Immunotherapy
		11.2.3 Parasite Immunotherapy
		11.2.4 Natural Products
	11.3 Avenues for Immunotherapy
		11.3.1 Neurodegenerative Diseases
		11.3.2 Infectious Diseases
		11.3.3 Autoimmune Diseases
		11.3.4 Other Applications
	11.4 Challenges and Limitations of Immunotherapies
	11.5 Translation of Immunotherapies: From Bench to Bed
	11.6 Conclusion
	References