Cancer Immunotherapies : Solid Tumors and Hematologic Malignancies

Preface
Acknowledgements
Introduction
Contents
1 Development of Cancer Immunotherapies
	1.1 Cancer Immunotherapy—Precision Medicine
	1.2 Immune Surveillance and Recognition of Cancer
	1.3 Cancer Immunoediting
	1.4 Tumor Antigens
		1.4.1 Tumor-Specific Antigens
		1.4.2 Tumor-Associated Antigens
	1.5 Methods of Tumor Antigen Identification
		1.5.1 Gene Expression Profiling
		1.5.2 Serological Screening for Antibody-Targeting Antigens
		1.5.3 Recognition by Reactive Patient Lymphocytes
	1.6 Tumor Immune Evasion
	1.7 Passive Immunotherapy
		1.7.1 Tumor-Specific Antibodies
		1.7.2 Immune Checkpoint Inhibitors
		1.7.3 Adoptive T Cell Therapies
	1.8 Active Immunotherapy
		1.8.1 Prophylactic Cancer Vaccines
		1.8.2 Therapeutic Cancer Vaccines
	1.9 Conclusion
2 Melanoma: An immunotherapy journey from bench to bedside
	2.1 Introduction
	2.2 Immune Hallmarks of Melanoma
		2.2.1 Pre-clinical Rationale for Checkpoint Blockade
	2.3 Immunotherapy in Metastatic Cutaneous Melanoma
		2.3.1 The Development of Immunotherapy in Advanced Cutaneous Melanoma
	2.4 Adjuvant and Neoadjuvant Immune Checkpoint Inhibitor Therapy
		2.4.1 Adjuvant Immune Checkpoint Blockade
		2.4.2 Neoadjuvant Immune Checkpoint Blockade
	2.5 Immunotherapy in Specific Contexts
		2.5.1 Uveal Melanoma
		2.5.2 Mucosal Melanoma
		2.5.3 Melanoma with Brain Metastases
	2.6 Pharmacology of Immune Checkpoint Blockade
		2.6.1 Pharmacokinetics of ICBs
		2.6.2 Dose and Scheduling of ICBs
		2.6.3 Therapeutic Drug Monitoring
	2.7 Response and Resistance to Immune Checkpoint Blockade
		2.7.1 Somatic Genotype and Immune Phenotype
		2.7.2 Predictors of Response
		2.7.3 Mechanisms of Resistance
	2.8 Beyond the Checkpoint
		2.8.1 Harnessing the Innate and Adaptive Immune Systems
		2.8.2 Small Molecules
		2.8.3 IL-2
		2.8.4 DNA-Damaging Agents
		2.8.5 Adoptive Cell Therapy
		2.8.6 Epigenetics
3 Engaging Pattern Recognition Receptors in Solid Tumors to Generate Systemic Antitumor Immunity
	3.1 Pattern Recognition Receptors (PRRs) Induce Innate Inflammation
	3.2 PRR Signaling Dictates CD8+ T Cell Priming, Recruitment, and Function During Viral Infection
	3.3 The Cancer Immunity Cycle and PRR Signaling
	3.4 Endogenous Activation of PRRs in Cancer
	3.5 Engaging PRRs for Cancer Immunotherapy
		3.5.1 Inducing Innate Inflammation in Tumors: A Historical Perspective
		3.5.2 Non-Infectious Engagers of PRRs for Cancer Immunotherapy
		3.5.3 Infectious Agents as Engagers of PRRs for Cancer Immunotherapy
	3.6 The Role of Type I IFN in Mediating the Antitumor Efficacy of PRR Agonists
	3.7 Comparison of PRR Activators to Other Immunotherapies and Their Utility in Combination
	3.8 The Future of PRR-Targeted Cancer Immunotherapies: Hurdles and Limitations
4 Allogeneic Tumor Antigen-Specific T Cells for Broadly Applicable Adoptive Cell Therapy of Cancer
	4.1 Introduction
	4.2 Tumor Antigen-Reactive T Cells Emerging Post-DLI
	4.3 Development of Tumor Antigen-Targeted Immunotherapies
		4.3.1 Minor Histocompatibility Antigens
		4.3.2 Self-antigens Differentially Highly Expressed by Tumors
		4.3.3 Tumor-Exclusive Neoantigens
		4.3.4 Use of Multi Tumor-Antigen Specific T Cells
		4.3.5 Tumor Antigens Recognized by Unconventional T Cells
	4.4 Technological Advances Facilitating Tumor Antigen Discovery and Evolution of More Effective and Persistent Tumor-Selective T Cells
	4.5 Towards a Broadly Applicable Cell Therapy for Cancer
5 Chimeric Antigen Receptor (CAR) T Cell Therapy for Glioblastoma
	5.1 CAR T Cells: A Novel Cell Therapy for Cancer
		5.1.1 Structure and Manufacturing
		5.1.2 Clinical CAR T Cell Success in Hematologic Malignancies
	5.2 Glioblastoma: Current Barriers and the Promise for CAR T Cells
		5.2.1 The Blood-Brain-Barrier
		5.2.2 Low Tumor Mutational Burden and Antigen-Processing Machinery Defects
		5.2.3 Immunosuppressive Tumor Microenvironment
	5.3 CAR T Cell Therapy for Glioblastoma
		5.3.1 Epidermal Growth Factor Receptor Variant III
		5.3.2 Human Epidermal Growth Factor Receptor 2
		5.3.3 IL-13 Receptor Subunit Alpha 2
		5.3.4 Alternative GBM-Associated Targets for CAR T Cell Therapy
	5.4 Optimizing CAR T Cell Therapy for Glioblastoma
		5.4.1 Overcoming the Immunosuppressive Glioblastoma Microenvironment
		5.4.2 Battling Tumor Heterogeneity
		5.4.3 Enhancing CAR T Cell Trafficking
	5.5 Concluding Remarks and the Path Forward
6 Lag3: From Bench to Bedside
	6.1 Introduction
	6.2 Preclinical Evidence Supporting the Benefit of LAG-3 Inhibition
	6.3 Preclinical Evidence Supporting the Benefit of Dual Inhibition of LAG-3 and Other Immune Checkpoints
	6.4 Agents Targeting LAG-3 Used in Preclinical Models
	6.5 Clinical Evidence Demonstrating the Efficacy of LAG-3 Targeting in Cancer
	6.6 LAG-3 as a Prognostic Biomarker in Solid Tumors
	6.7 Conclusions and Future Directions
7 Immunotherapy in Genitourinary Malignancy: Evolution in Revolution or Revolution in Evolution
	7.1 Background
	7.2 Immunotherapy in Urothelial Carcinoma
	7.3 Immunotherapy in Renal Cell Carcinoma
	7.4 Immunotherapy in Prostate Cancer
	7.5 Immunotherapy in Testicular Cancer
	7.6 Immunotherapy in Penile Cancer
	7.7 Perioperative Immunotherapy as Window of Opportunity to Cure—Paradigm-Changing
	7.8 Conclusion
	References
8 Immune-Based Therapeutic Interventions for Acute Myeloid Leukemia
	8.1 Introduction
	8.2 Immune Checkpoint Inhibitors Reactivating Endogenous T Cell Responses
	8.3 Bispecific Antibodies Recruiting T Cells Independently of T Cell Receptor (TCR) Specificity
	8.4 Chimeric Antigen Receptor (CAR) T Cells Redirecting T Cell Specificity
	8.5 Vaccines
	8.6 Adoptive NK-Cell Therapies
	8.7 Monoclonal Antibodies
	8.8 Active Areas of Research
9 Off-the-Shelf Chimeric Antigen Receptor Immune Cells from Human Pluripotent Stem Cells
	9.1 The History of CAR-T Therapy
	9.2 The Achievements and Existing Problems About CAR-T Therapy
	9.3 Generation of CAR-immune cells from PSCs (examples, advances)
	9.4 Potential and Perspectives of CAR-Immune Cells in Cancer Treatment
	9.5 Future Prospects
10 The Single-Cell Level Perspective of the Tumor Microenvironment and Its Remodeling by CAR-T Cells
	10.1 Introduction of the Tumor Microenvironment (TME)
	10.2 Tumor-Associated Macrophages in TME
	10.3 Cellular and Molecular Features that Determine the Response to CAR-T Cells
	10.4 Single-Cell Sequencing Combined with the Different Approaches Uncovers TME
	10.5 Strategies of CAR-T Remodel the TME
	10.6 Prospective
11 Clinical Development and Therapeutic Applications of Bispecific Antibodies for Hematologic Malignancies
	11.1 Introduction
	11.2 The Construction of Bispecific Antibodies and Their Cellular Properties
	11.3 Clinical Outcomes of BiTE in Hematologic Malignancies
	11.4 Development of Blinatumomab
	11.5 Acute Lymphoblastic Leukemia
		11.5.1 Administration and Dosing Schedules
		11.5.2 BCP-ALL in CR with MRD and R/R BCP-ALL [3]
		11.5.3 Predictive Indicators for Blinatumomab Treatment in R/R B-ALL
		11.5.4 Adverse Events Associated with Blinatumomab in ALL
		11.5.5 Resistance to Blinatumomab and BITEs
	11.6 Resistance Mechanisms
		11.6.1 T Cell Exhaustion/Dysfunction
	11.7 Acute Myeloid Leukemia
	11.8 Multiple Myeloma
		11.8.1 Clinical Development for MM (CD38-CD3)
		11.8.2 Clinical Development for MM (FcRL5-CD3 and GPRC5D-CD3)
	11.9 Non-Hodgkin Lymphoma
	11.10 Dual Affinity BsAbs and Tandem Diabodies
	11.11 Combination and Sequential Therapies [3]