Lipid A In Cancer Therapy (advances In Experimental Medicine And Biology)

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. Title Page 4 Copyright Page 5 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

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.

Structure and synthesis of lipid A / Shoichi Kusumoto, Masahito Hashimoto and Kazuyoshi Kawahara Conformation and supramolecular structure of lipid A / Klaus Brandenburg and Ulrich Seydel Interactions between lipid A and serum proteins / Jèorg Andrèa ... [et al.] The lipid A receptor / Kiyoshi Takeda Lipid A receptor TLR4-mediated signaling pathways / Masahiro Yamamoto and Shizuo Akira Lipid A-induced responses in vivo / Néjia Sassi ... [et al.] Lipid A-mediated tolerance and cancer therapy / Cheryl E. Rockwell, David C. Morrison and Nilofer Qureshi Lipid A in cancer therapies : preclinical results / Daniele Reisser and Jean-François Jeannin Monophosphoryl lipid A (MPL) as an adjuvant for anti-cancer vaccines : clinical results / Christopher W. Cluff Antitumoral effects of lipids A : clinical studies / Marc Bardou and Danièle Reisser. Structure and synthesis of lipid A / Shoichi Kusumoto, Masahito Hashimoto and Kazuyoshi Kawahara Conformation and supramolecular structure of lipid A / Klaus Brandenburg and Ulrich Seydel Interactions between lipid A and serum proteins / Jørg Andrø ... [et al.] The lipid A receptor / Kiyoshi Takeda Lipid A receptor TLR4 mediated signaling pathways / Masahiro Yamamoto and Shizuo Akira Lipid A induced responses in vivo / Nøjia Sassi ... [et al.] Lipid A mediated tolerance and cancer therapy / Cheryl E. Rockwell, David. C. Morrison and Nilofer Qureshi Lipid A in cancer therapies : preclinical results / Daniele Reisser and Jean-François Jeannin Monophosphoryl lipid A (MPL) as an adjuvant for anti-cancer vaccines : clinical results / Christopher W. Cluff Antitumoral effects of lipids A : clinical studies / Marc Bardou and Danièle Reisser. Front Matter....Pages i-vii Introduction: Historical Background....Pages 1-3 Structure andSynthesis of Lipid A....Pages 5-23 Conformation and Supramolecular Structure of Lipid A....Pages 25-38 Interactions between Lipid A and Serum Proteins....Pages 39-51 The Lipid A Receptor....Pages 53-58 Lipid A Receptor TLR4-Mediated Signaling Pathways....Pages 59-68 Lipid A-Induced Responses In Vivo....Pages 69-80 Lipid A-Mediated Tolerance and Cancer Therapy....Pages 81-99 Lipid A in Cancer Therapies Preclinical Results....Pages 101-110 Monophosphoryl Lipid A (MPL) as an Adjuvant for Anti-Cancer Vaccines: Clinical Results....Pages 111-123 Antitumoral Effects of Lipids A, Clinical Studies....Pages 125-131 Conclusion....Pages 133-134 Back Matter....Pages 135-136