ESMO HANDBOOK OFIMMUNO-ONCOLOGYESMO HANDBOOK OFIMMUNO-ONCOLOGYEdited byJohn B.A.G. HaanenThe Netherlands Cancer Institute, Amsterdam, NetherlandsIwona LugowskaMaria Sklodowska-Curie Memorial Cancer Centre-Institute of Oncology (MSCMI), Department of Soft Tissue/Bone Sarcoma and Melanoma, Warsaw; Institute of Mother and Child, Department of Epidemiology, Warsaw, PolandMarina Chiara GarassinoMedical Thoracic Oncology Unit, Department of Medical Oncology and Hematology, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, ItalyRaffaele CalifanoDepartment of Medical Oncology, The Christie NHS Foundation Trust, Manchester; Department of Medical Oncology, Manchester University NHS Foundation Trust, Manchester; Division of Cancer Sciences, The University of Manchester, Manchester, UKESMO Press First published in 2018 by ESMO Press© 2018 European Society for Medical OncologyAll rights reserved. No part of this book may be reprinted, reproduced, transmitted, or utilised in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission of the publisher or in accordance with the provisions of the Copyright, Designs, and Patents Act 1988 or under the terms of any license permitting limited copying issued by the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, USA (copyright/ or telephone 978-750-8400). Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe.This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the authors and publisher cannot assume responsibility for the validity of all materials or for the consequence of their use.Although every effort has been made to ensure that drug doses, treatments, and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publisher nor the authors can be held responsible for errors or for any consequences arising from the use of information contained herein. For detailed prescribing information on the use of any product or procedure discussed herein, please consult the prescribing information or instructional material issued by the manufacturer.A CIP record for this book is available from the British Library.ISBN: 978-88-941795-7-6For orders, corporate sales, foreign rights, and reprint permissions, please contact:ESMO Head OfficeGuidelines, Publishing and Online Education DepartmentVia Ginevra 46900 LuganoSwitzerlandTel: +41 (0)91 973 19 00esmoEmail: publishingesmoPrinted through s|s|media limited, Rickmansworth, Hertfordshire, UKvContentsEditors xiiContributors xviReviewers xxiiAbbreviations xxvAcknowledgements xxxiiiPreface xxxivSection 1: Introduction to immunology and immunotherapy1.1 Immune Checkpoints 3Definition 3Immune Synapse 4Technical Procedures 7Predictive and/or Prognostic Biomarkers of (Potential) Clinical Relevance 8Clinical Results 10Potential Future Developments 13Further Reading 141.2 Adoptive T Cell Therapy 15Naturally Occurring Tumour-specific T Cells 15Genetically Modified T Cells 17Concluding Remarks 22Further Reading 22vi1.3 Vaccines (Dendritic Cell Vaccines, Peptide Vaccines, DNA Vaccines, RNA Vaccines, Oncolytic Viruses) 23Definition (Introduction to the Concept and Development of Cancer Vaccine Strategies) 23Essential Processes Involved 26Dendritic Cell Vaccines 27Peptide Vaccines 31DNA Vaccines 34RNA Vaccines 35Oncolytic Viruses 36Predictive and/or Prognostic Biomarkers of (Potential) Clinical Relevance 37Potential Future Developments 37Further Reading 401.4 Biomarkers for Immunotherapy 43Introduction 43Biological Background for Biomarkers in Immunotherapy 43Future Immuno-oncology Biomarker Strategies 53Conclusion 53Further Reading 541.5 Resistance to Immunotherapy 56Introduction 56Tumour-intrinsic Mechanisms of Immune Checkpoint Inhibitor Resistance 57Tumour-extrinsic Mechanisms of Immune Checkpoint Inhibitor Resistance 63Environmental Host Factors 64Unmet Needs 66Further Reading 67Section 2: Immunotherapies in specific disease groups State of the art2.1 Melanoma 73Overview of Immunotherapy in Melanoma 73ContentsviiImmunotherapy in Metastatic/Unresectable Melanoma 74Adjuvant Immunotherapy in Melanoma 79Immunotherapy Versus Targeted Therapy 81The Endless Search for a Biomarker 82Future Perspectives 83Further Reading 852.2 Merkel Cell Carcinoma 87Overview 87Introduction 87Immunology of MCC 88Immunotherapy of MCC 90Unmet Needs and Future Directions 94Conclusion 96Further Reading 962.3 Thoracic Malignancies 2.3.1 Non-small Cell Lung Cancer 99Current Scope of Immunotherapy of NSCLC 99Predictive Biomarkers of Immunotherapy Response of Clinical Relevance 100Immunotherapy of Locally Advanced NSCLC 105Immunotherapy of Early-stage NSCLC 105Potential Future Developments 107Further Reading 1112.3.2 Small Cell Lung Cancer 112Introduction 112Rationale for Immunotherapy in SCLC and Predictors of Response 114Clinical Results 115Future Developments 118Further Reading 1232.3.3 Mesothelioma 125Definition 125Predictive and/or Prognostic Biomarkers of Clinical Relevance 125ContentsviiiClinical Results 126Potential Future Developments 129Further Reading 1312.3.4 Other Thoracic Malignancies: Thymic Malignancies and Others 133Thymic Malignancies 133Other Rare Thoracic Malignancies 138Further Reading 1402.4 Genitourinary Malignancies2.4.1 Renal Cancer 142Introduction 142Clinical Results 143Potential Future Developments 148Conclusion 151Further Reading 1522.4.2 Bladder Cancer 154Introduction and Context 154Clinical Results 156Potential Future Developments 161Further Reading 1642.5 Gastrointestinal Malignancies2.5.1 Microsatellite Instability-high 166Pathogenesis of Microsatellite Instability 167Who Does This Apply To? 168Clinical, Pathological and Genetic Criteria Involved in Detection of Mismatch Repair Deficiency 169Historical Prognostic and Predictive Value of MSI 171Clinical Rationale of Using MSI as a Predictive Biomarker for Programmed Cell Death Protein 1 Antibody Response 172Clinical Implications 173Further Reading 175Contents2.5.2 Gastric and Oesophageal Malignancies 178Introduction 178The Immune Environment in Gastro-oesophageal Cancer 178Immune Checkpoint Blockade in Gastro-oesophageal Cancer 179Squamous Oesophageal Cancer 187Conclusions and Future Directions 188Further Reading 1892.5.3. Hepatocellular Carcinoma 191Introduction 191HCC Immunobiology 192Current Landscape of Immune Checkpoint Inhibition in HCC 193Alternative Immunotherapeutic Strategies 198Future Directions and Issues Specific to HCC 199Conclusions 201Further Reading 2022.6 Immunotherapy in Head and Neck Tumours (HPV+and HPV-) 203Immunotherapy in Head and Neck Cancer the Rationale 203Immunotherapy for Locally Advanced Head and Neck Squamous Cell Carcinoma 205Immunotherapy in Recurrent/Metastatic Head and Neck Cancer Evidence and Future Directions 208Immuno-oncology in Head and Neck Cancer: Predictive Biomarkers? 210Conclusion 214Further Reading 2142.7 Immunotherapies in Lymphoma 217Introduction 217Monoclonal Antibodies 217Interferons 219Vaccination 220Immune Checkpoint Inhibitors 221Chimeric Antigen Receptor-T cell Therapy 224Bispecific Antibodies 227Further Reading 228ixContentsx2.8 Gynaecological Malignancies 230The Role of Immunotherapy in Ovarian Cancer 230The Role of Immunotherapy in Cervical Cancer 235The Role of Immunotherapy in Endometrial Cancer 238Further Reading 241Section 3: Implications for clinical practice3.1 Management of Adverse Events Related to Immune Checkpoint Blockade 245Definition 245Processes Involved 245Global Management 246Clinical Results 247Further Reading 2563.2 Immune Checkpoint Blockade: Response Patterns and Assessment of Response 258The Problem 258Response Patterns in Immunotherapy 258Criteria for Response 261Potential Future Developments 264Further Reading 2663.3 Immunotherapy in Special Populations 267Introduction 267Clinical Results/Patient Groups 268Potential Future Developments 275Further Reading 2763.4 Cancer Immunotherapy Trials: Challenges and Opportunities 278Introduction 278Lessons from Pre-checkpoint Inhibitor Immunotherapy 280Optimising Contemporary Immunotherapy Clinical Trials 282Summary 285Further Reading 286Contents3.5 Future Perspectives 287Introduction 287Precision Immunotherapy 288Conclusions 294Further Reading 295Index 296xiContents