Immune Strategies for Gastrointestinal Cancer (Cancer Immunotherapy, 2)

Immunotherapy in GI Cancers: Introduction
Contents
Part I: Role of the Tumor Microenvironment
	An Overview of the Tumor Microenvironment and Response to Immunotherapy in Gastrointestinal Malignancies
		1	 An Overview of Gastrointestinal Malignancies
		2	 Key Players in the Tumor Microenvironment
		3	 Cancer and Stromal Cell Cross-Talk: Role of Epithelial to Mesenchymal Transition
		4	 Tumor Microenvironment: The Role of Tumor-Associated Macrophages (TAM)
		5	 New Interest in Cancer Immunology: Myeloid-Derived Suppressor Cells (MDSCs)
		6	 Adaptive Immunity in Cancer Immunotherapy
		7	 Natural Killer (NK) Cells as a Novel Frontier in Cancer Immunotherapy
		8	 Dendritic Cells (DCs) Link the Innate and Adaptive Immune System
		9	 Targeting the Tumor Microenvironment to Enhance Clinical Immunotherapy
		10	 The Tumor Microenvironment and Response to Immunotherapy in GI Malignancies
		11	 Concluding Remarks
		References
Part II: Esophagus
	Approach to Immunotherapy in Oesophageal Cancer
		1	 Background
		2	Oesophageal Squamous Cell Cancer
			2.1	Single-Agent Anti-PD-1 Antibodies
			2.2	 Anti-PD-1 Antibodies in Combination with Other Systemic Therapies
			2.3	 Early Disease
		3	Oesophageal Adenocarcinoma
			3.1	Single-Agent Anti-PD-1 Antibodies
			3.2	 Anti-PD-1 Antibodies in Combination with Other Systemic Antibodies
			3.3	Early Disease
		4	 Concluding Remarks
		References
	Perspective on the Immunotherapy of Esophageal Cancer
		1	 Introduction
		2	 The Suppressed Immune Microenvironment of ESCC and EAC and Response to Immunotherapy
		3	 Stromal Derived Immune Modulation
		4	 Checkpoint Inhibition and Conventional Anti-Cancer Treatments in Esophagogastric Cancer: New Roads Ahead?
		5	 Immunotherapy Beyond Checkpoint Inhibitors
		6	 Microbiome
		7	 Concluding Remarks
		References
Part III: Stomach
	Immunotherapy of Gastric Cancer: Focus on Perioperative Strategies
		1	 Introduction
		2	 Role of Targeted Therapies
		3	 Rational for Immunotherapy
		4	 Biomarkers of Immunotherapy
		5	 Immunotherapy for MSI Locally AGC
		6	 Immunotherapy for HER2+ GC
		7	 Immune Strategies for Resectable Non-MSI Non-HER2+ GC
		8	 Adjuvant Immunotherapy in Oesophageal-Gastric Cancer
		References
	Stomach: The Standard of Care ± HER2
		1	 Introduction
		2	 Molecular Subtypes in Gastric Cancer
		3	 Chemotherapy for Advanced Gastric Cancer
		4	 Role of Angiogenesis Blockade in Metastatic Gastric Cancer
		5	 Targeting HER2
		6	 Immunotherapy for Gastric Cancer
		7	 Conclusion
		References
	Perspective on the Immunotherapy of Gastric Cancer
		1	 Biomarkers of ICIs in Gastric Cancer
			1.1	 PD-L1 CPS
			1.2	 Microsatellite Instability-High
			1.3	 Tumor Mutation Burden
			1.4	 Epstein–Barr Virus (EBV)
			1.5	 Others
				1.5.1	 Hyperprogressive Disease
				1.5.2	 Gene Expression Signatures
		2	 Combined Immunotherapy
			2.1	 ICIs Plus Chemotherapy
			2.2	 ICI Doublet: Anti-PD-1/PD-L1 Antibody Plus Anti-CTLA4 Antibody
			2.3	 Anti-HER2 Antibody Plus Immune Checkpoint Inhibitors
			2.4	 ICIs and VEGF Inhibitors
			2.5	 ICIs and Local Therapies
			2.6	 ICIs and Other Targeted Agents
				2.6.1	 ICI and PARP Inhibitor
				2.6.2	 ICI and DKN-01
			2.7	 Others (CAR-T and BiTEs)
		3	 Conclusion
		References
Part IV: Colon
	Immunotherapy in dMMR/MSI-H Colon Cancer
		1	 Introduction
		2	 Evidence for Immunotherapy in dMMR/MSI-H CRC
			2.1	 Monotherapy with PD-1 Inhibitors
			2.2	 Combination of PD-1 and CTLA-4 Inhibitors
			2.3	 Combination of PD-L1 Inhibitor with Anti-angiogenic VEGF-Antibody
				2.3.1	 Ongoing Clinical Trials
		3	 Conclusions and Perspective
		References
	Immunotherapy in the Treatment of Advanced Colorectal Cancer
		1	 Introduction
		2	 Role of the Immune System in Colorectal Cancer
		3	 Strategies to Overcome ICI Resistance in pMMR/MSS Colorectal Cancer
			3.1	 BRAF/MAPK
			3.2	 VEGF Inhibitors
			3.3	 EGFR Inhibitors
			3.4	 MEK Inhibitors
			3.5	 POLE Mutations
			3.6	 IDO Inhibitors
			3.7	 Carcinoembryonic Antigen T-Cell Bispecific Protein
			3.8	 Toll-Like Receptor Agonists
			3.9	 Radiation Therapy
			3.10	 Costimulatory Receptor Agonists
		4	 Conclusion and Future Direction
		References
	Immunotherapy of Rectal Cancer
		1	 Introduction
		2	 Biology of Rectal Cancer
		3	 Completed Clinical Trials of Immunotherapy for Rectal Cancer
		4	 Ongoing Clinical Trials of Immunotherapy for Rectal Cancer
		5	 Conclusion
		References
	Perspective on Immunotherapy of Colon Cancer: Challenges for the Future
		References
Part V: HCC
	Immune Strategies for Gastrointestinal Cancer: HCC
		1	 Introduction
		2	 Hepatic Immunobiology
		3	 Implications for HCC Classification and Treatment
		4	 Immunotherapy and HCC
			4.1	 Immune Checkpoint Blockade as Monotherapy
			4.2	 Immunotherapy-Based Combinations
				4.2.1	 Anti-VEGF plus Checkpoint Inhibitors
					Atezolizumab and Bevacizumab Combination
				4.2.2	 TKI and Checkpoint Inhibitor
					Pembrolizumab and Lenvatinib
					Ipilimumab and Nivolumab with Cabozantinib
					Pembrolizumab and Regorafenib
					Atezolizumab and Lenvatinib or Sorafenib
				4.2.3	 Combinations of Checkpoint Inhibitors
					Durvalumab and Tremelimumab
					Ipilimumab and Nivolumab
		5	 Locoregional Therapies and Immune System
		6	 Conclusion
		References
	Immunotherapy in GI Cancers: Hepatocellular Carcinoma: Perspective
		References
Part VI: Biliary Tract
	Immunotherapy of Biliary Tract Cancer
		1	 Biliary Tract Cancer
		2	 Microenvironment and Immune Landscape in Biliary Tract Cancer
			2.1	 Cell Populations of the Innate Immune Response
			2.2	 Components of the Adaptive Immune Response
		3	 Molecular Subgroups of Biliary Tract Carcinoma in the Context of Immunotherapy
			3.1	 Targetable Molecular Alterations in Biliary Tract Carcinoma
			3.2	 FGFR2 Alterations
			3.3	 IDH1/IDH2 Mutations
			3.4	 Homologous Recombination Deficiency (HRD)
			3.5	 Mismatch Repair Deficiency (dMMR/MSI-H)
			3.6	 Other Targetable Molecular Subgroups of BTC
		4	 Immunotherapy for BTCs: Reported Clinical Outcomes
			4.1	 Anti-PD1/PD-L1 Immune Checkpoint Inhibitor Monotherapy
			4.2	 Anti-PD1/PD-L1 Plus Anti-CTLA-4 Combination Regimens
			4.3	 Immune Checkpoint Inhibitors in Combination with Chemotherapy
			4.4	 Anti-PD1/PD-L1 Immune Checkpoint Inhibitors in Combination with Small-Molecule Inhibitors
			4.5	 Novel Immunotherapeutic Agents Evaluated for BTCs
			4.6	 T Cell Therapies, Tumor Vaccines, and Oncolytic Viruses
		5	 Summary and Outlook
		References
	Perspective on Immunotherapy Use in Biliary Tract Cancer
		1	 Introduction
		2	 Monotherapy
		3	 Strategies for Overcoming Primary resistance
		4	 Combined PD-1 and CTLA-4 Inhibition
		5	 Chemotherapy in Combination with ICIs
		6	 Targeted Treatment in Combination with ICIs
		7	 GM-CSF in Combination with ICIs
		8	 Bintrafusp alfa
		9	 Localised Therapies in Combination with ICIs
		10	 Microsatellite Instability-High Tumours
		11	 Expert Opinion
		References
Part VII: Pancreas
	Immune Landscape of Pancreas Ductal Adenocarcinoma: Current Therapeutic Strategies and Future Perspective
		1	 Background
		2	 Immune Checkpoint Blockade (ICB)
			2.1	 Combined Chemo-Immunotherapy Approaches
			2.2	 CD40 Agonism
			2.3	 Immune Checkpoint Blockade and DNA Damage Response
			2.4	 Purinergic Signaling and Immunotherapy
		3	 Adoptive Cell Therapy
		4	 Therapeutic Vaccines
			4.1	 Cancer Vaccines and a Renewed Approach to Target KRAS
		5	 Targeting the Tumor Microenvironment
			5.1	 Targeting Tumor-Adjacent Immunosuppressive Cells
			5.2	 Targeting Stromal Elements
		6	 Autophagy Inhibition
		7	 Future Perspectives
		References
	Perspective on the Immunotherapy of Pancreatic Cancer
		1	 Introduction
		2	 Cancer Vaccines
		3	 Checkpoint Inhibitors
		4	 Inhibition of Suppressive Myeloid Cells
		5	 Overcoming the Suppressive Tumor Microenvironment
		6	 T Cell Cellular Therapy
		7	 Conclusions and Future Directions
		References
Part VIII: Biomarkers for Immunotherapy in Gastrointestinal Cancers
	Biomarkers for Immunotherapy in Gastrointestinal Cancers
		1	 Introduction
		2	 Main Biomarkers for Immunotherapy in GI Cancers
			2.1	 Microsatellite Instability/Mismatch Repair Deficiency
			2.2	 Tumor Mutational Burden
			2.3	 PD-L1 Status
		3	 Colorectal Cancer
			3.1	 Microsatellite Instability/Mismatch Repair Deficiency
			3.2	 Tumor Mutational Burden
			3.3	 POLE and POLD1 Mutations
			3.4	 PD-L1 Status
			3.5	 Tumor-Infiltrating Lymphocytes and Immunoscore
		4	 Gastric Cancer
			4.1	 PD-L1 Status
			4.2	 Microsatellite Instability/Mismatch Repair Deficiency
			4.3	 Epstein–Barr Virus Status
			4.4	 Tumor Mutational Burden
			4.5	 Gene Expression Signatures
			4.6	 Neutrophil-to-Lymphocyte Ratio
		5	 Other GI Cancers
			5.1	 Esophageal Carcinoma
			5.2	 Anal Cancer
			5.3	 Hepatocellular Carcinoma
			5.4	 Pancreatic Adenocarcinoma
		6	 Conclusion
		References