Lipid A in Cancer Therapy (eBook)

Jean-Francois Jeannin (Herausgeber)

eBook Download: PDF

2010 | 2010
152 Seiten
Springer New York (Verlag)
978-1-4419-1603-7 (ISBN)

Infos

Cancer remains a major challenge for modern society. Not only does cancer rank among the first three causes of mortality in most population groups but also the therapeutic options available for most tumor types are limited. The existing ones have limited efficacy, lack specificity and their administration carry major side effects. Hence the urgent need for novel cancer therapies. One of the most promising avenues in research is the use of specific immunotherapy.

The notion that the immune system may have important anti-tumor effects has been around for more than a century now. Every major progress in microbiology and immunology has been immediately followed by attempts to apply the new knowledge to the treatment of cancer. Progress has reached a point where it is well established that most cancer patients mount specific T cell responses against their tumors. The molecular identity of the antigens recognized by anti-tumor T cells has been elucidated and several hundreds of tumor-derived antigenic peptides have been discovered. Upon recognition of such peptides presented by self MHC molecules, both CD8 and CD4 T cells are activated, expand to high numbers and differentiate into effective anti-tumor agents. CD8 T cells directly destroy tumor cells and can cause even large tumors to completely regress in experimental mouse models. These observations have spurred intense research activity aimed at designing and testing cancer vaccines.

Over 100 years ago Coley successfully used intratumoral injection of killed bacteria to treat sarcomas. The important anti-tumor effects observed in a fraction of these patients fueled major research efforts. These led to major discoveries in the 80s and the 90s. It turns out that bacterial lipopolysaccharides stimulate the production of massive amounts of a cytokine still known today as tumor necrosis factor (TNF-a). They do so by engagement of a rather complex set of interactions culminating in the ligation of a Toll-like receptor, TLR -4. Ensuing signaling through this receptor initiates potent innate immune responses. Unfortunately the clinical use of both TNF-a and LPS can not be generalized due to their very narrow therapeutic margin. Importantly, synthetic Lipid A analogs have been identified that retain useful bioactivity and yet possess only mild toxicity.

The relatively large body of information accumulated thus far on the molecular and cellular interactions set in motion by administration of LPS as well as by the synthetic lipid A analogs allow to place this family of bacterially-derived molecules at the crossroads between innate and adaptive immunity. By virtue of this key position, the therapeutic applications being pursued aim at using these compounds either as direct anti-tumor agents or as vaccine adjuvants. The clinical experience acquired so far on these two avenues is asymmetric. Few clinical trials using Lipid A analogs as single anti-cancer agents involving less than 100 patients with advanced cancer have been reported. In contrast, lipid A has been tested in over 300,000 individuals in various vaccines trials, including therapeutic cancer vaccines.

Clearly most of the work needed to develop lipid A as effective anti-cancer agents and/or as vaccine adjuvant lies ahead in the near future. This book is a timely contribution and provides a much needed up-to-date overview of the chemical, biological and physiological aspects of lipid A. It should be a beacon to all those involved in this field of research.

Jean-François Jeannin is Professor of Immunology at Ecole Practique des Hautes Etudes (EPHE) and director of the EPHE Tumor Immunology and Immunotherapy Laboratory, an INSERM (National Institute of Health and Medical Research) team. His main research interests have included the effects of lipopolysaccharides in the tumor immune response and the immunotherapy of colon cancer with lipid A. Now he is investigating mechanisms of immunotherapy with synthetic lipid A analogs in cancer patients and animal cancer models. He is especially interested in the sensitization of tumor cell death by nitric oxide produced in tumors during lipid A immunotherapy.

Jean-François Jeannin has been Dean and President of the Life Sciences faculty of EPHE and a member of numerous scientific organizations.

Inhalt

FOREWORD 6
ABOUT THE EDITOR... 8
PARTICIPANTS 9
Table of Contents 12
CHAPTER1 Introduction: Historical Background 16
References 18
CHAPTER 2 Structure and Synthesis of Lipid A 19
Introduction 19
General Architecture of Lipid A 20
Chemical Structure of Lipid A from Escherichia coli and Salmonella 20
General Structure of Lipid A 21
Structural Variations of Lipid A 23
Variation of Acyl Groups: Locations, Typesand Chain Lengths 23
Modifications of the Phosphate Moiety 27
Unusual Lipid A 28
Chemical Synthesis of Lipid A 31
Conclusion 33
References 33
CHAPTER 3 Conformation and Supramolecular Structure of Lipid A 38
Abstract 38
Introduction 38
Aggregate Structure and Molecular Conformation 40
Intramolecular Conformation 41
Phase States and Transitions between Them 42
Molecular Modelling 44
Physicochemical Data in Relation to Biological Activity 45
Conformational Concept of Lipid A Action: How Does Endotoxin Interact with Immune Cells? 46
References 49
CHAPTER 4 Interactions between Lipid A and Serum Proteins 52
Abstract 52
Proteins Involved in Lipid A/LPS-Mediated Immune Cell Activation 52
Detection of Lipid A by Immunoglobulins 54
Proteins Involved in Lipid A/LPS Transport 54
Serum Albumin 54
Lipoproteins 55
Proteins Neutralizing the Immune-Cell Activating Properties of Lipid A/LPS 57
Lactoferrin 57
Bactericidal/Permeability-Increasing Protein (BPI) and LPS-Binding Protein (LBP) 58
Cathelicidins 58
Conclusion 59
References 59
CHAPTER 5 The Lipid A Receptor 65
Abstract 65
Introduction 65
Components of the Lipid A Receptor 65
LBP and CD14 65
TLR4 66
MD-2 66
RPI05 and MD-I 68
Conclusion 68
References 69
CHAPTER 6 Lipid A Receptor TLR4-Mediated Signaling Pathways 71
Abstract 71
Introduction 71
The MyD88-Dependent and MyD88-Independent Pathways 72
TRIF: The TIR Domain-Containing Signal Transducer for the MyD88-Independent Pathway 72
TIRAP and TRAM: Another Two TIR Domain-Containing Molecules 74
Negative Regulation of LPS-Induced Signaling Pathways 74
Two-Step Gene Induction Program in TLR4-Mediated 76
Immune Responses 76
Conclusion 77
References 77
CHAPTER 7 Lipid A-Induced Responses In Vivo 81
Abstract 81
Fate of Lipid A in the Bloodstream 81
General Immune Responses to Lipid A 82
Inflammatory Response 82
Other Responses 82
AdaptiveImmune Response 82
B-Cells and Antibody Production 82
Dendritic Cells 83
T-Cells 83
Systemic Toxicity 83
Lipid A Tolerance 84
Tumor Immune Responses 85
Molecular Immune Response 85
Cellular Immune Responses 86
Cells of the Innate Immune System 86
Cells of the Adaptive Immune Response 87
Vascular Response 87
Conclusion 88
References 88
CHAPTER 8 Lipid A-Mediated Tolerance and Cancer Therapy 93
Abstract 93
Early, Late and Cross Tolerance 93
The Isolation of Various Lipid A Structures and Synthesis of Analogs 94
Relevance of Tolerance to the Use of LPS/Lipid A in Cancer 95
LPS in Clinical and Animal Studies 95
Monophosphoryl Lipid A and Lipid A Adjuvants 97
Synthetic Lipid A Analog, ONO-4007 97
Synthetic Compound, DT-5461 98
Synthetic Compound, SDZMRL 953 98
Mechanisms of EarlyLPS/Lipid A-Mediated Tolerance 98
Toll-Like Receptors, Associated Signaling Molecules and Negative Regulators 99
Corticosteroids, Anti-Inflammatory Cytokines and Prostaglandins 101
Transcriptional Mediators 101
The Role of the Proteasome 102
Mechanisms of Tolerance of Other Lipid A Structures and LPS Antagonists 103
Conclusion 103
References 105
CHAPTER 9 Lipid A in Cancer Therapies Preclinical Results 112
Abstract 112
Introduction 112
LPS Treatments 112
Lipids A Treatments 113
DT-5461 114
ONO-4007 115
OM-174 117
Conclusion 118
References 119
CHAPTER 10 Monophosphoryl Lipid A(MPL) as an Adjuvant for Anti..Cancer Vaccines:Clinical Results 122
Abstract 122
Section 1: Vaccines Targeting Specific Cancer Types 123
Vaccines Targeting Colorectal Carcinoma 123
Vaccines Targeting Prostate Cancer 123
Vaccines Targeting Melanoma 124
Vaccines Targeting HER2-Positive Breast Carcinoma 126
Section 2: Vaccines Targeting Specific TAAs Expressed on Multiple Tumor Types 126
Vaccines Targeting MAGE-3-Expressing Cancers 126
Vaccines Targeting MUCI-Expressing Cancers 127
Vaccines Targeting STn-Expressing Carcinomas 128
Vaccine Targeting Ras-E xpressing Tumors 130
Conclusion 130
References 131
CHAPTER 11 Antitumoral Effects of Lipids A,Clinical Studies 135
Abstract 135
Introduction 135
Immunological Background Underlying the Clinical Potential Interest 136
Clinical Studies 137
Conclusion 139
References 139
CHAPTER 12 Conclusion 142
References 143
INDEX 144

Produkt-Details

• Erscheint lt. Verlag: 28.7.2010
• Reihe/Serie: Advances in Experimental Medicine and Biology
• Reihe/Serie: Advances in Experimental Medicine and Biology
• Zusatzinfo: 152 p. 20 illus.
• Verlagsort: New York
• Sprache: englisch
• Themenwelt: Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
• Themenwelt: Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie
• Schlagworte: Antigen • Biology • Cancer • Jeanin • Lipid • Medicine • therapy
• ISBN-10: 1-4419-1603-2 / 1441916032
• ISBN-13: 978-1-4419-1603-7 / 9781441916037