Provides readers with a clear understanding of the value and challenges of using common and emerging preclinical models in cancer immunotherapy research and development.
Animal models are essential tools for studying a range of issues in preclinical and clinical research on therapies targeting cancerous tumors. As clinical trials of advances in cancer immunotherapy are predicted to outpace preclinical research in the near future, there remains an urgent need to develop better animal models for preclinical evaluation of novel modulators. Animal Models for the Development of Cancer Immunotherapy provides a detailed overview of different preclinical model systems for development of novel cancer immunotherapies while highlighting how key aspects of individual models translate into clinical findings.
Covering the introduction, development, and therapeutic applications of animal models for cancer immunotherapy, this comprehensive volume helps pharmacologists identify suitable animal models, design pharmacological or translational studies, and advance their mechanistic understanding of therapeutic agents, and increase the possibility of success for novel immunotherapies in clinical settings. Chapters written by prominent leaders in the field address specific models that evaluate immuno-oncology drugs are supported by in-depth case studies and extensive references throughout. - Emphasizes the importance of modeling tumor metastasis in preclinical models for efficient translation of findings into the clinic - Explores recently discovered mechanisms of resistance and their preclinical modeling - Highlights the unique characteristics and features of autologous and allogeneic approaches for humanization of mouse models - Reviews development of bone marrow-liver-thymus (BLT) immune humanized mice and emerging alternative models such as genetically engineered mouse models (GEMM) - Discusses alternative animal models for cancer research such as severe combined immunodeficiency (SCID) pigs
Animal Models for the Development of Cancer Immunotherapy is an essential resource for scientists and researchers in the pharmaceutical and biotechnology industries, medicinal chemists and biochemists, cell and molecular biologists, pharmacologists, immunologists, and clinicians.
Table of Contents
List of Contributors xiii
Introduction 1
Mithun Khattar and Karuppiah Kannan
Tumor 3
Host 5
Modality 7
References 9
1 Transplantable Syngeneic Murine Tumor Models 11
Rich Woessner, Alexandra Borodovsky, Kris Sachsenmeier, Felix Scheuplein, Robert W. Wilkinson, Chaoyang Ye and Simon Dovedi
1.1 Introduction 11
1.2 Overview of Syngeneic Murine Tumor Models 14
1.2.1 Immunological Diversity in Syngeneic Models 14
1.2.2 Technical and Experimental Design Considerations 24
1.2.2.1 Timeline of Immune Response 24
1.2.2.2 Lab to Lab Variations 25
1.2.2.3 Housing and Husbandry Conditions 25
1.2.2.4 Age and Source of Mice 25
1.2.2.5 Microbiome Effects 26
1.2.2.6 Checkpoint Antibodies 26
1.2.2.7 Site of Implantation 27
1.3 Modeling the Immune Suppressive Tumor Microenvironment with Syngeneic Models 28
1.3.1 Immune Suppressive Metabolites 28
1.3.2 Immune Suppressive Cell Populations 30
1.3.2.1 Myeloid‐Derived Suppressor Cells 31
1.3.2.2 Tumor‐Associated Macrophages 32
1.3.2.3 Regulatory T Cells 33
1.3.2.4 Regulatory B Cells 34
1.3.2.5 Concluding Remarks 34
1.4 Genomic Analysis/Bioinformatics for Syngeneic Tumor Models 35
1.4.1 Background 35
1.4.2 Traditional Methods 35
1.4.2.1 Immunohistochemistry and Immunofluorescence 35
1.4.2.2 In Silico Imputation 37
1.4.3 Medium throughput methods 38
1.4.4 High‐Throughput Methods: scRNAseq 38
1.4.5 Multi‐omics Methods 39
1.4.6 Data Analysis 39
1.4.7 Technical and Sample Considerations 40
1.4.8 Challenges and Translation into Clinic 40
1.5 OT‐1 Systems and OVA Expressing Tumor Models for Understanding the Effect of Immuno‐Oncology (I‐O) Agents on T‐Cell Responses 41
1.6 Modeling Chemotherapy/Radiation Therapy + Immunotherapy Combinations with Syngeneic Models 43
1.6.1 Preclinical Modeling of Radiotherapy/Immunotherapy Combinations 44
1.6.2 Preclinical Modeling of Chemotherapy/Immunotherapy Combinations 45
1.6.3 Summary 46
1.7 Conclusions 46
References 48
2 Genetically Engineered Mouse Models (GEMMs) in Cancer Immunotherapy R&D
Zhao Chen 63
2.1 Current Challenges in Immuno-oncology In vivo Modeling 63
2.2 Pros and Cons of GEMM in Immuno-oncology Studies 67
2.3 Organoid-Based GEMM Tumors 68
2.4 Modeling Different TME Using GEMM 70
2.5 In vivo Target ID Based on GEMM 71
2.6 Modeling Immune System Functions with GEMM 71
References 72
3 Mouse Tumor Homografts Recapitulate Human Molecular Pathogenesis 75
Rajendra Kumari, Davy Ouyang and Henry Li
3.1 Introduction 75
3.2 Transplanted Syngeneic Cell Line Models 76
3.3 Spontaneous Autochthonous Mouse Models 78
3.4 Mouse-Derived Tumor Homografts 81
3.5 Generation of Tumor Homografts 83
Protocol 83
3.6 Orthotopic Implantation 87
3.7 Pancreatic Cancer Homografts 88
3.8 Prostate Cancer Homografts 94
3.9 Large Scale Mouse Clinical Trial Using Homografts 99
3.10 Limitations with Regard to Usage of Murine Tumor Homografts 101
3.11 Summary 101
Acknowledgments 102
References 102
4 Modeling Resistance to Immune Checkpoint Blockade 107
Michael Quigley, Matthew J. Meyer and Kanstantsin Katlinski
4.1 Introduction 107
4.2 The Use of Preclinical Mouse Models to Understand Mechanisms of Resistance to Checkpoint Blockade 110
4.3 Lack of Inflammation 112
4.4 Inadequate Antigenicity 114
4.5 Suppressive Immune Cell Populations 117
4.6 Compensatory T-Cell Checkpoints 120
4.7 Suppressive Stromal Factors 125
4.8 Tumor-Intrinsic Mechanisms of Resistance to Checkpoint Blockade 127
4.9 Identification of New Mechanisms of Resistance and Opportunities for Therapeutic Intervention 131
4.10 Conclusion 133
References 134
5 Orthotopic Mouse Models of Colorectal Cancer and Imaging Techniques 151
Ce Yuan, Xianda Zhao, Dechen Wangmo, Travis J. Gates and Subbaya Subramanian
5.1 Introduction 151
5.2 Orthotopic Model 152
5.2.1 Model Establishment 152
5.2.2 Surgical Tumor Implantation in the Cecum 152
5.2.3 Endoscopy-Guided Intra-colon Wall Tumor Cell Injection 154
5.2.4 Immune Features 154
5.2.5 Metastasis Features 155
5.2.6 Advantages and Limitations 155
5.3 Imaging Techniques 156
5.3.1 Small Animal Endoscopy 156
5.3.2 Magnetic Resonance Imaging 157
5.3.3 Positron Emission Tomography 158
5.3.4 Imaging Tumor-Specific Markers 158
5.3.5 Bioluminescent Imaging (BLI) 159
5.3.6 Imaging Immune Cells 160
5.4 Summary and Future Directions 160
Acknowledgments 162
References 163
6 Preclinical Osteoimmuno-Oncology Models to Study Effects of Immunotherapies on Bone Metastasis 167
Tiina E. Kähkönen, Jussi M. Halleen and Jenni Bernoulli
6.1 Introduction to Metastasis and Use of Preclinical Models 167
6.2 Bone Metastatic Microenvironment 169
6.2.1 Introduction to Bone Biology 169
6.2.2 Immune Cells in the Bone Marrow 170
6.2.3 Osteoimmunology 172
6.2.4 Immunotherapies and Bone Safety 174
6.2.5 Vicious Cycle of Bone Metastasis 175
6.2.6 Immune Cells in Regulating Metastasis to Bone 175
6.2.7 Effects of Estrogens and Androgens on Cancer, Bone, and Immune System 177
6.3 Bone Metastasis Models 178
6.3.1 Conventional Models to Study Bone Metastasis 178
6.3.2 Novel Bone Metastasis Models 180
6.3.3 Imaging Techniques in Bone Metastasis Models 181
6.3.3.1 Bioluminescence and Fluorescence Imaging and Injectable Dyes 181
6.3.3.2 X-ray Imaging 183
6.3.3.3 Micro-computed Tomography 186
6.3.3.4 Tumor Biomarkers and Bone Turnover Markers 188
6.3.3.5 Novel Imaging Techniques 189
6.3.3.6 Histology and Immunohistochemistry 189
6.3.3.7 Analysis of Immune Cells: Flow Cytometry and Immune Cell Tracking 191
6.3.4 What Models to Choose and Readouts to Include in a Bone Metastasis Study? 193
6.4 Syngeneic Bone Metastasis Models 194
6.4.1 Breast Cancer 194
6.4.2 Prostate Cancer 195
6.4.3 Multiple Myeloma and Lymphoma 196
6.4.4 Osteosarcoma 197
6.4.5 Lung and Bladder Cancer 197
6.5 Humanized Mouse Models of Bone Metastasis 198
6.5.1 Breast Cancer 199
6.5.2 Prostate Cancer 200
6.6 Conclusions and Future Directions 200
References 201
7 Humanized Mouse Models for Cancer Immunotherapy: A Focus on Human PBMC and HSPC Reconstitution 211
Zhuo Li, Xiao Yang and Xiaomin Song
7.1 Immunocompromised Mice 211
7.1.1 An Evolving History of Mouse Strains 212
7.1.2 Emerging Strain Variants 213
7.2 Human Immune System (HIS) Models 221
7.2.1 Hu-PBMC Model 221
7.2.2 Hu-CD34+ HSPC Model 226
7.3 Tumors of Human Origin 229
7.3.1 Patient-Derived Xenograft (PDX) 229
7.3.2 Conditionally Reprogrammed PDX (CR-PDX) Cells 230
7.4 Applications of HIS Mice in I-O Research 231
7.4.1 Hu-PBMC Tumor Efficacy Model 231
7.4.2 Hu-CD34+ HSPC Tumor Efficacy Model 232
7.4.3 Considerations of HIS Tumor Models 233
7.4.4 Preclinical Safety Evaluation in HIS Mice 234
7.5 Future Perspectives 235
7.5.1 Creating Human Tumor Microenvironment (TME) in HIS Mice 235
7.5.2 Combining Patient PBMCs and Tumors in HIS Mice 236
7.5.3 Human Microbiota-Associated Mice 236
References 237
8 Bone Marrow-Liver-Thymus (BLT) Humanized Mice as a Tool to Assess Checkpoint Inhibitor Adverse Events 251
Kenrick M. Semple, Alan D. Knapton and Kristina E. Howard
References 260
9 Development of Swine Models for Cancer Research: SCID Pigs and Other Emerging Pig Cancer Models 263
Adeline N. Boettcher and Christopher K. Tuggle 263
9.1 The Emergence of New Swine Biomedical Models 263
9.2 Overview of Existing Swine Biomedical Models 264
9.2.1 ARTEMIS Deficient SCID Pigs 264
9.2.2 RAG1 and RAG2 Knockout SCID Pigs 265
9.2.3 IL2RG Knockout SCID Pigs 266
9.2.4 Double Mutant SCID Pigs 266
9.2.5 Inducible TP53and KRAS Mutant Pigs 267
9.3 Overview of Existing and Emerging Cancer Models in Pigs 267
9.3.1 B-Cell Lymphoma 268
9.3.2 Breast Cancer 268
9.3.3 Colorectal Carcinoma 269
9.3.4 Glioblastoma 269
9.3.5 Hepatocellular Carcinoma 270
9.3.6 Melanoma and Histiocytoma 270
9.3.7 Osteosarcoma 271
9.3.8 Ovarian Cancer 272
9.3.9 Pancreatic Cancer 272
9.4 Immunotherapy Models to Develop in Pigs 272
9.4.1 Humanized SCID Pigs and Xenograft Models 273
9.4.2 Transplant Models in Immunocompetent Swine 274
9.4.3 Immunotherapeutic Models to Be Developed in Swine Models 274
9.4.3.1 Dendritic Cell Vaccines 274
9.4.3.2 T- and NK-Cell Therapy Testing 275
9.4.3.3 Personalized Xenograft Models in SCID Pigs 276
9.4.3.4 Immunometabolism Targeting 276
9.5 SCID Pig Housing 277
9.5.1 Biocontainment and Biosecurity 277
9.5.2 Farrowing, Caesarean-Sections, Piglet Care, and Microbiota 277
9.6 Concluding Remarks and Future Directions 278
List of Abbreviations 279
References 279
Index 287
