Principles of Cancer Biotherapy (eBook)

Principles of Cancer Biotherapy 1
Title Page 2
Copyright Page 3
Preface 4
Contents 6
Contributors 8
Chapter 1 11
Cancer biotherapy: general principles 11
Historical Perspectives 11
Preclinical Models 14
Biological Activity in Preclinical Models 14
Model Screening Criteria 14
Evaluation of Screening Programs 14
Biotherapy: Specific Agents and Approaches 15
Nonspecific Immunomodulators 15
Active Specific Immunotherapy 16
Thymic Factors 17
Recombinant DNA Technology 17
Lymphokines/Cytokines 18
Growth and Maturation Factors 20
Monoclonal Antibodies 22
Future Perspectives 23
References 23
Chapter 2 27
The pathogenesis of cancer metastasis: relevance to therapy 27
Introduction 27
The Pathogenesis of Cancer Metastasis 27
Neovascularization-Angiogenesis 28
Tumor Cell Invasion 30
Lymphatic Metastasis 30
Hematogenous Metastasis 31
Metastasis of Metastases 32
The Biologic and Metastatic Heterogeneity of Neoplasms 32
Enhanced Metastatic Potential of Tumor Cells Harvested from Metastases 33
Clonal Origin of Cancer Metastases 33
Development of Biological Diversity within and Among Metastases 34
Intratumoral Heterogeneity for Expression of Tyrosine Kinase Growth Factor Receptors 35
Zonal Heterogeneity for Gene Expression 35
Tumor-Organ Interaction: The “Seed and Soil” Hypothesis 36
Regulation of Tumor Cell Gene Expression by the Organ Microenvironment 37
Regulation of the Invasive Phenotype by the Microenvironment 38
Regulation of Angiogenesis by the Organ Microenvironment 38
Influence of Lymphoid Cells on Angiogenesis 39
Regulation of Response to Chemotherapy by the Organ Microenvironment 39
Targeting the Vasculature 40
Targeting the Expression of Platelet-Derived Growth Factor Receptor by Reactive Stroma 40
Anti-Vascular Therapy of Prostate Cancer Bone Metastasis 42
Targeting Platelet-Derived Growth Factor Receptor on Endothelial Cells of Multidrug Resistant Prostate Cancer 42
Conclusions 44
References 44
Chapter 3 51
Developmental therapeutics and the design of clinical trials 51
Drug Development 52
Biologicals and BRM Development 54
Interferons: the Early Model 55
Biotherapy Trial Strategies 55
Empirical Clinical Testing 56
Escalating dose Trials Using Different Groups of Patients 56
Escalating-dose Trials within Individual Patients 56
Schedule 57
Route 57
Patient Selection 58
Future Prospects 58
References 60
Chapter 4 63
Recombinant proteins and genomics in cancer therapy 63
Introduction 63
Isolation, Cloning and Expression of Genes 63
Recombinant Proteins as Cancer Therapeutics 66
Cytokines 67
Interferons 67
Interleukins 70
Other Interleukins 72
Colony-Stimulating Factors 72
Tumor Necrosis Factors 73
Soluble Cytokine Receptors 74
Genomics and Proteomics in Cancer Therapeutic 75
Oligonucleotide Arrays for Quantitative Analysis of > 30,000 Unique mRNAs
cDNA Arrays are Dotted Arrays of PCR Amplified Products of Cloned Genes 76
Proteomic Analysis and Cancer 77
Antibodies and Conjugates 77
Monoclonal Antibodies as Agonists 78
Monoclonal Antibodies-Conjugated Drugs 78
Immunotoxins 79
Monoclonal Antibodies and Radioimmunotherapy 81
Chimeric Proteins 81
Cancer Vaccines 81
Problems Unique to Recombinant Biotherapeutics 83
Delivery of Therapeutic Proteins 84
Conclusions 85
References 85
Chapter 5 94
Current concepts in immunology 94
Current Concepts of Immunity 94
T lymphocytes 97
T-helper Cells 99
T-suppressor Cells 99
T-cytotoxic Cells 100
B lymphocytes 100
Monocytes and Macrophages 101
Natural Killer Cells 101
Lymphokine-activated Killer Cells 102
Clinical Assessment of Immune Competence 102
In Vivo 102
Delayed Type Hypersensitivity (DTH) 102
Humoral Immunity 103
Reticuloendothelial System 103
In Vitro 103
Immune Cell Quantitation 103
Lymphoproliferative Responses 103
Cytotoxicity 104
Lymphokine Production 104
Immunoglobulin Production 104
Phagocytic Cell Function 104
Immunoregulatory Cell Functions 104
Quality Control of in vitro Assays 105
References 105
Chapter 6 109
Therapeutic approaches to cancer-associated immune suppression 109
Immunosuppression and Cancer 109
Multifactorial Basis of Immunodeficiency in Cancer Patients 110
Effector Cell Numbers and Function 110
Immunoregulatory Cells 111
Immunomodulatory Factors 112
Immunosuppression and Tumor Cell Burden 113
Solid Tumors 113
Delayed-Type Hypersensitivity (DTH) 113
Lymphoproliferative Responses (LPR) 113
Immune Cell Quantitation 114
Cytolytic Functions 114
Antibody Formation 115
Phagocytic Cell Function 115
Correlations Among Immune Cell Numbers and Function 115
Hematopoietic Malignancies 115
Prognostic Implications of Immunosuppression 116
Solid Tumors 116
Hematopoietic Malignancies 117
Perioperative Immunosuppression 117
Perioperative Blood Transfusion 117
Radiation Therapy-induced Immunosuppression 118
Chemotherapy-induced Immunosuppression 119
Antimetabolites 119
Alkylating Agents 120
Antitumor Antibiotics 120
Vinca Alkaloids and Podophyllotoxins 121
Other Drugs 121
Hormones 121
Combination Chemotherapy 121
Immune Status of Patients in Clinical Remission 122
Solid Tumors 122
Hematopoietic Malignancies 122
Treatment of Cancer-associated Immunodeficiency 123
Immunorestorative Agents 123
Chemicals 123
Histamine Receptor Antagonists 124
Nonsteroidal Anti-inflammatory and Antipyretic Agents (NSAID) 125
NPT 15392 125
Biologicals 125
Thymic Factors 125
T-cell Reconstituting Factor 126
Transfer Factor 127
Interleukins 127
Retinoids 127
Treatment of Cancer-associated Immunosuppression: Phase I and II Studies 128
Chemicals 128
Hodgkin’s Disease 128
Solid Tumors 129
Biologicals 129
Hodgkin’s Disease 129
Malignant Melanoma 129
Chronic Lymphocytic Leukemia (CLL) 130
Phase II/III Surgical Adjuvant Studies 130
Chemicals 130
Lung Cancer 130
Gastrointestinal Cancer 130
Phase III Levamisole Trials in Colon Cancer 130
Gynecologic and Urologic Cancer 130
Malignant Melanoma 131
Biologicals 131
Lung Cancer 131
Head and Neck Cancer 131
Malignant Melanoma 131
Treatment of Radiotherapy-induced Immunosuppression 131
Chemicals 131
Levamisole 131
Isoprinosine 132
Prostaglandin Antagonists 132
Biologicals 133
Thymic Factors 133
Transfer Factor 133
T-cell Reconstituting Factor 133
Retinoids 133
Bestatin 134
OK-432 134
Combined-modality Studies with Chemotherapy 134
Advanced Disease 134
Chemicals 134
Levamisole 134
Prostaglandin Inhibitors 136
Cimetidine 136
Biologicals 136
Thymic Factors 136
Lentinan 136
Bestatin 136
Adjuvant Chemotherapy 136
Chemicals 137
Levamisole 137
Biologicals 137
Transfer Factor 137
OK-432 137
Thymic Factors 137
Current Status of Therapeutic Alterations for Cancer-associated Immune Suppression 137
References 138
Chapter 7 154
Cancer vaccines 154
Introduction 154
Approaches to Cancer Vaccines 154
Pitfalls in Developing Cancer Vaccines 155
Mechanisms to Improve the Immune Response 156
Cancer Prevention Vaccines 156
Therapeutic Cancer Vaccines 156
Conclusion 158
References 159
Chapter 8 161
Cytokines 161
Cytokine Receptors: Many Belong to Receptor Families 161
Toll-Like Receptors and the Response to LPS 169
The Helper T Cell System 169
Antigen Presentation Dendritic Cells
Tumor Necrosis Factor Family of Cytokines 171
Interleukin-1 171
Inflammation, Immune Regulation, Hematopoiesis, and Wound Repair 171
Interleukin-2 175
Growth And Activation of T, B and NK Cells Activation-Induced Cell Death
Interleukin-3 177
Hematopoietic Cytokine 177
Interleukin-4 178
B Cell and T Helper Response 178
Interleukin-5 180
Eosinophil Growth/Differentiation Inflammation
Interleukin-6 180
Hematopoiesis, Thrombopoiesis, Inflammation 180
Interleukin-7 183
T Cell, B Cell, Macrophage and Dendritic Cell Development 183
Interleukin-8 185
Chemotaxis, Angiogenesis 185
Interleukin-9 186
Mast Cell, T Cell, Lymphoma Growth Factor Inflammatory
Interleukin-10 186
Regulator of Immune Response 186
Interleukin-11 188
Hematopoietic Progenitor/Thrombocytosis Stimulator Regulator of Inflammation
Interleukin-12 189
Immune Stimulation, Inflammation, Hematopoiesis, Regulator of Innate and Adaptive Immunity 189
Interleukin-13 191
Regulation of Inflammation Allergy
Interleukin 14 192
B Cell Development and Memory 192
Interleukin 15 192
NK Cell Activity, Maintenance of T Cell Memory 192
Interleukin-16 193
Chemoattractive Proinflammatory
Interleukin-17A 195
Proinflammatory, Hematopoietic, Neutrophil Development 195
Interleukin-17B 196
Proinflammatory Cytokine 196
Interleukin-17C 197
Proinflammatory Cytokine 197
Interleukin-17D 197
Proinflammatory, Inhibitor of Hematopoiesis 197
Interleukin-17E: see Interleukin-25 Interleukin-17F 197
Proinflammatory, Asthma, Inhibitor of Angiogenesis 197
Interleukin-18 197
Interferon Gamma, NK and Th1 Response, Regulation of Inflammation 197
Interleukin-19 199
Inflammation 199
Interleukin-20 200
Inflammation, Skin Development and Immunity 200
Interleukin-21 200
NK, T and B Cell Development, Immunomodulation 200
Interleukin-22 201
Inflammation 201
Interleukin-23 201
T cell Stimulation, Inflammation, Regulator of Adaptive and Innate Immunity 201
Interleukin-24 202
Interleukin-25 202
Proinflammatory Regulation of Th17
Interleukin-26 203
Epithelial Immune Response 203
Interleukin-27 203
Adaptive and Innate Immune Response Regulation of Inflammation/Th17
Interleukin-28A, Interleukin-28B, Interleukin-29 203
Type III Interferons Antiviral, Antitumor
Interleukin-31 204
Pruritis, Allergic Inflammation 204
Interleukin-32 204
Inflammation 204
Interleukin-33 204
Inflammation, Allergy 204
Interleukin-35 205
Treg Cytokine, Regulation of Th17 205
4-1BB Iigand 205
Costimulation of T Cells, T Cell Memory 205
CD27 ligand 206
Costimulation of T and B Cells B Cell Differention
CD30 ligand 206
T Cell Costimulation, Selection Apoptosis
CD40 ligand 207
Costimulatory, Proinflammatory B, and T Cell Stimulation
Chemokines 209
Cell Activation, Migration, and Recruitment Inflammation
Fas ligand 210
Inducer of Apoptosis 210
FLT-3 ligand 210
Stimulator of Early Hematopoietic Stem Cells and Dendritic Cells 210
Leukemia inhibitory factor 212
T Cell Development, Regulator of Inflammation, Embryonic Development 212
LIGHT 213
Costimulatory Molecule T Cell Activator
Lymphotoxin-Alpha (Tumor Necrosis Factor Beta) 213
Lymphoid Organogenesis Inflammation
Lymphotoxin-Beta 214
Lymphoid Organogenesis Inflammatory
Novel neurotrophin 215
B Cell Development Regulator of Inflammation
Oncostatin M 215
Lymph Node/T Cell Development Inflammation
Osteopontin 216
Pro Th1, Nitric Oxide Synthetase Inhibiting Cytokine 216
OX40 ligand 217
Costimulation in T Cell, B Cell Development/Memory Inflammation
RANKL/TRANCE 218
B Cell, DC, Osteoclast Development, Lymph Node Organogenesis 218
Stem cell factor 218
Early Progenitor and Mast Cell Growth Factor 218
Tumor Necrosis Factor Alpha 219
Inflammation, Immune Regulation, Apoptosis, Endothelial Damage 219
TRAIL 222
Apoptosis in Neoplastic Cells Regulation of Inflammation
TWEAK 222
Cell Growth, Survival Angiogenesis
References 223
Abbreviations 282
Chapter 9 283
Interferons: therapy for cancer 283
Nomenclature 283
Clinical use 285
B Cell Malignancy 285
Hairy Cell Ieukemia 285
Multiple Myeloma 286
Non-Hodgkin’s lymphoma (NHL) 287
Other lymphomas 290
Chronic Myeloid leukemia (CML) 290
Interferon Monotherapy Early Studies
Randomized Studies of Interferon Monotherapy Versus Chemotherapy 291
Interferon in combination with cytotoxic drugs in the treatment of CML 291
Solid Tumors 292
Kaposi’s Sarcoma 292
Melanoma 293
Advanced Disease 293
Adjuvant Therapy 293
Renal Carcinoma 294
Other Solid Tumors 295
Mode of Action 296
Antiproliferative 296
Antiviral Activity 296
Immune Modulation 297
Differentiation 298
Anti-Angiogenesis 298
Side Effects 299
Summary 299
References 299
Chapter 10 308
Monoclonal antibody therapy 308
Background and Rationale for Antibody Therapy 308
Historical aspects 1900–1980 308
Antisera Trials 1925–1980 310
Animal Models and Antibody Therapy 310
Human Trials with Murine Monoclonal Antibodies 1980–1989 310
Antibodies and Antigens 311
Unconjugated Antibodies as Therapeutic Agents 312
Manufacturing of Monoclonal Antibodies 312
Hybridoma Technology 312
Recombinant Technology and Engineering Monoclonal Antibodies 314
Human Monoclonal Antibodies 314
Chimeric and Humanized Monoclonal Antibodies 315
Antibodies with Multiple Specifi cities and/or Functions 316
Monoclonal Antibody Nomenclature 316
Mechanisms of Antibody-Mediated Anti-Tumor Effects 316
Complement Mediated Cytotoxicity 317
Antibody Dependent Cell-Mediated Cytotoxicity 317
Regulatory Approaches 318
Idiotype Network 318
Epidermal Growth Factor and its Receptors (EGF and EGFR) 319
Vascular Endothelial Growth Factor and its Receptors 320
Considerations for Clinical use of Monoclonal Antibodies as Cancer Therapy 320
Antitumor Effects 320
In Vivo Binding to Malignant Cells 320
Clinical Effi cacy and Mechanisms 321
Adverse Events: Toxicity and side Effects 322
Infusion Reactions 323
Tumor lysis Syndrome 324
Acute Hypersensitivity Reactions and Anaphylaxis 325
Side Effects Secondary to Binding to Non-Malignant Tissues 325
Immune complexes 326
Delayed Allergic Reactions and Serum Sickness 326
Antibody Issues 326
Immunoglobulin Class and Subclass 326
Human Anti-Immunoglobulin Response 326
Antigen issues 327
Antigenic Modulation 327
Free Antigen 328
Antigen Heterogeneity 328
Dose, Schedules, and Pharmacokinetics 328
Antibody Dose 328
Infusion Rates/Schedules 329
Serum Levels and Pharmacokinetics 329
Commercially Available Unconjugated Mab for Treatment of Human Malignancy 330
Rituximab (Rituxan®, Biogen-Idec Pharmaceuticals, San Diego, CA and Genentech, South San Francisco, CA) 330
Rituximab and CD20 330
Clinical Trials with Rituximab Early Clinical Trials with Single-Agent Rituximab 331
Rituximab in Follicular Lymphoma 331
Rituximab in Small Lymphocytic Lymphoma 332
Rituximab in Marginal Zone Lymphoma 332
Rituximab in Lymphoplasmacytic Lymphoma 333
Rituximab in Large B Cell Lymphoma 333
Rituximab in Mantle Cell Lymphoma 333
Rituximab in Chronic Lymphocytic Leukemia 334
Rituximab in Hairy Cell Leukemia 334
Rituximab in Multiple Myeloma 334
Rituximab in Hodgkin’s Disease 335
Extended therapy and Maintenance Rituximab 335
Rituximab with Chemotherapy 337
Indolent and Follicular Lymphoma 337
Chemotherapy and Rituximab in Chronic Lymphocytic Leukemia 338
Large B Cell Lymphoma 338
Mantle Cell lymphoma 340
Burkitt’s Lymphoma and ALL 341
HIV Associated Lymphoma 341
Central Nervous System Lymphoma 342
Maintenance Rituximab following Chemotherapyor Rituximab Plus Chemotherapy 342
Rituximab with other Biologics 343
Rituximab with Biologicals other than Monoclonal Antibodies 343
Rituximab with other monoclonal antibodies 343
Toxicity and side Effects 344
Summary 344
Alemtuzumab (Campath®, Bayer Healthcare, Tarrytown, NY) 345
Alemtuzumab and CD52 345
Clinical Trials with Alemtuzumab 345
Alemtuzumab with Chemotherapy in CLL 347
Alemtuzumab with other Biologicals in CLL 347
Toxicity and Side Effects 347
Summary 347
Trastuzumab (Herceptin®, Genentech, South San Francisco, CA) 348
Trastuzumab and Her2 348
Clinical Trials with Trastuzumab in Breast Cancer 349
Trastuzmab Alone 349
Trastuzumab Plus Single-Agent Chemotherapy 350
Combination Chemotherapy and Trastusumab 350
Randomized Trials of Chemotherapy With or Without Trastuzumab in Breast Cancer 351
Adjuvant Treatment of Breast Cancer 352
Trastuzumab and Hormonal Therapy for Breast Cancer 353
Trastuzumab in Other Tumor Types 353
Trastuzumab with other Biologicals 354
Toxicity and Side Effects 354
Summary 355
Bevacizumab (Avastin®, Genentech, South San Francisco, CA) 355
Bevacizumab and Vascular Endothelial Growth Factor 355
Clinical Trials with Bevacizumab 356
Mechanisms of Anti-Tumor Activity 361
Toxicities and Adverse Events 361
Summary 361
Cetuximab (Erbitux®), Bristol-Myers Squibb 361
Cetuximab and the Epidermal Growth Factor Receptor 361
Clinical Trials with Cetuximab 362
Mechanisms of Anti-Tumor Activity and Toxicity 365
Summary 366
Panitumumab (Vectibix™) Amgen, Thousand Oaks, California 366
Panitumumab and EGFR 366
Clinical Trials with Panitumumab 366
Toxicities 367
Summary 368
Conclusions 368
Other Antibodies and Antigens 368
Anti-Idiotype Antibodies 368
Antigens Associated with Hematopoietic Cells 369
CD3 369
CD4 370
CD5 370
CD10 371
CD15 371
CD19 371
CD20 371
CD22 372
CD23 372
CD25 372
CD30 373
CD33 374
CD38 374
CD40 374
CD45 374
CD74 375
CD80 375
CD122 375
HLA DR 375
HM1.24 375
Anti CTLA4 (Cytotoxic T Lymphocyte Antigen 4) 375
Tumor Necrosis Factor-Related Apoptosis- Inducing Ligand (Trail) Receptor 376
Nuclear Factor-Kappa B Ligand 377
Integrins 377
Human Epidermal Growth Factor Receptor Antigens (EGFR1) 377
Human Epidermal Growth Factor Receptor Antigens (EGFR2) 378
Insulin-Like Growth Factor Receptor 379
Transferrin Receptor 379
Vascular Ligands and Receptors 380
Carcinoembryonic Antigen (CEA) 380
Epithelial Cell Adhesion Molecule (EpCAM) 380
CA125 383
Other Anti-Adenocarcinoma Monoclonal Antibodies 383
G250 (CAIX, MN/CA9) Renal Cell Cancer Antigen 385
Prostate Cancer Associated Antigens 385
Melanoma and Neuroectodermal Associated Antigens 385
Other Ligand Targets 388
Anti-Idiotype Vaccines 389
Anti-Idiotype Vaccines in Adenocarcinomas 389
Anti-Idiotype Vaccines in Melanoma 390
1E10 Anti-Idiotype Vaccines to Gangliosides 390
Summary 390
References 390
Chapter 11 412
Immunotoxins 412
Introduction 412
Peptide Cytotoxins 412
Type I plant A-B Toxins 412
Type I plant A toxins 413
Type I Bacterial A-B Toxins 414
Type I Bacterial Binary Toxin 418
Type I Vertebrate A Toxins 419
Type I Fungal A Toxins 420
Type II Toxins 420
Type III Toxins 420
Toxin Modification and Ligand Conjugation 421
Toxin Modification 421
Ligand Selection 421
Conjugation of Toxin and Ligand 431
Preclinical Studies with Immunotoxins 431
Clinical Experience with Immunotoxins 432
Effi cacy 432
Pharmacokinetics and Tissue Distribution 434
Immune Responses 434
Toxicities 434
Ongoing and Future Clinical Studies 435
References 436
Cgapter 12 455
Drug Immunoconjugates 455
The Problem of Heterogeneity: Antibody-Based Therapeutics as a Solution 455
Rationale for Immunoconjugates 456
Rationale for Antitumor Cocktails 457
Clinical-Laboratory Integration for Drug Immunoconjugate Trials 459
Chemotherapeutic Drug Immunoconjugates 459
Pre-Clinical Studies 459
Clinical Trials 461
Conclusions 463
References 463
Chapter 13 467
Targeted radionuclide therapy of cancer 467
Introduction 467
Radionuclides for Radioimmunotherapy 467
Beta Particle Decay 468
Alpha Particle Decay 469
Emerging Radionuclides for use in RIT 469
Antibody-Based Radiopharmaceuticals 469
Radioimmunotherapy of Hematologic Tumors 470
Lymphoma 470
131I-Tositumomab 471
90Y-ibritumomab tiuxetan 472
High-dose Radioimmunotherapy with Stem Cell Support for Lymphoma 473
Leukemia 474
Beta emitting Radionuclides for RIT of Leukemia 474
Alpha Emitting Radionuclides for RIT of Leukemia 475
RIT of Non-Hematologic Tumors 476
Gastrointestinal Carcinomas 476
Other CEA-Expressing Cancers 476
Prostate Cancer 476
Breast Cancer 477
Glioma 478
Systemic Injection 478
Compartmental Injection 479
Intralesional 479
Intrathecal 479
Peptide-Based Radiopharmaceuticals 480
Regulatory Peptides and their Receptors 480
Radiolabeling of Peptides 481
Clinical Experience with Somatostatin Analogs 482
Other Somatostatin Analogs 483
Other Peptides for Tumor Targeting 483
Gastrin 483
Vasoactive Intestinal Peptide (VIP) 485
Neurotensin 485
Bombesin 485
Glucagon-like Peptide-1 (GLP-1) 485
Peptide Receptor Radionuclide Therapy (PRRT) 485
Strategies to Improve Outcome of RIT 486
Increasing Dose Intensity 487
Increase Radioactivity Administered 487
Improving the Effect of the Administered dose 487
Increasing Tumor Localization 487
Compartmental Administration 487
Increasing Vascular Permeability 488
Biological Response Modifiers 488
Increasing the Dose Rate 488
Increasing Radiation Sensitivity 489
Reducing the Exposure to Normal Tissues 489
Pretargeted RIT 490
Pretargeted RIT for Lymphoma and Leukemia 491
Summary 492
References 493
Chapter 14 501
Stem cell/bone marrow transplantation as biotherapy 501
Autologous Bone Marrow Transplantation 501
The Preparation of Bone Marrow for Transplantation in ABMT 502
Techniques to Eliminate Specific Subpopulations of Cells (Tumor Cells and Lymphocytes) from Marrow Specimens 502
Ex vivo Purging with Chemotherapy 502
Biophysical and Physical Approaches 503
Biotherapeutic Approaches 503
Combination Techniques 503
Stem-cell Selection 503
Allogeneic Bone Marrow Transplantation 504
Graft-versus-tumor Effects 504
Conclusion 505
References 505
Chapter 15 509
Cellular immunotherapy (CI), where have we been and where are we going? 509
Overview 509
A Recap of where the Field has been 509
Use of LAK and TIL in the Treatment of Cancer, are they gone Forever? 511
Lymphocyte Defined Tumor Associated Antigens (LDTAs) 513
Cancer Vaccines 514
Dendritic Cells and Vaccines 517
Treg Cells in Cancer: Biology and Potential Role in Tumor Immunity 519
Immunological Monitoring 520
Summary 521
References 522
Chapter 16 531
Growth and differentiation factors as cancer therapeutics 531
Human Leukemic Cell Lines as Models for Differentiation Therapy 532
Vitamin A Analogues as Leukemia Differentiation-Inducing Agents 536
Vitamin D Metabolites and Analogs as Leukemia Differentiation-Inducing Agents 544
Action of Vitamin D Metabolites on Cancer Cells 544
Receptors for Vitamin D and its Metabolites 547
Action of 1,25-(OH)2D3 on other Aspects of Hematopoiesis 548
In vivo Effects of Vitamin D Metabolites 548
Polar-Planar Compounds as Differentiation Inducers 550
Chemotherapeutic Agents as Differentiation Inducers 551
Molecular Mechanism Implicated in Leukemia Cell Differentiation 552
In vivo Induction of Differentiation with low-dose Cytosine Arabinoside or Azocytidine in Patients with acute Myeloid Leukemia and Myelodysplastic Syndrome (MDS) 552
Cytokines and Hematopoietic Growth Factors active in Regulating Proliferation and Differentiation of Leukemic Hematopoietic Cells 553
CSF-Dependence of Myeloid Leukemic Progenitors 554
Colony-Stimulating Factors as Leukemia Differentiating Agents 555
Interleukin 1 and Cell Proliferation and Differentiation 556
Interleukin-6 and Leukemic Cell Proliferation and Differentiation 556
Leukemia Inhibitory Factor 557
Tumor Necrosis Factor (TNFAlpha) and Lymphotoxin (TNFBeta) 558
Transforming Growth Factor Beta 559
References 561
Chapter 17 573
Granulocyte colony-stimulating factor: biology and clinical potential 573
Introduction 573
Biochemistry and Structure 573
Physiology 576
Pharmacokinetics 577
Healthy Volunteer Studies 577
Patients with Disease 577
Pharmacodynamics 578
Clinical Implications 578
Chemotherapy-induced Neutropenia 578
Bone Marrow or Stem Cell Transplantation 579
Severe Chronic Neutropenia 580
Bone Marrow Failure States 580
AIDS/HIV Infection 580
Current Issues 580
Immunomodulation 580
Use in Patients with Sickle-cell Anemia 581
Conclusions 581
References 581
Chapter 18 585
Granulocyte-macrophage colony-stimulating factor 585
Introduction 585
Biochemistry and Structure 585
Physiology 585
Pharmacology 586
Pharmacodynamics andPharmacokinetics 586
Clinical Implications 587
Chemotherapy-induced Neutropenia 587
Bone Marrow and Stem Cell Transplantation 587
Bone Marrow Failure States 587
Acute Leukemia 588
Current Issues 588
Use in Children 588
Immunomodulation 588
Vaccine Therapy 589
Conclusions 589
References 589
Chapter 19 593
Cancer gene therapy 593
Introduction 593
Gene Transfer Vectors 593
Retroviral Vectors 594
Adenoviral Vectors 595
Adeno-associated Viruses 595
Herpes Simplex Virus 595
Other Viral Vectors 596
Nonviral Vectors 596
Targeting of Viral Vectors 596
Transductional Targeting 596
Transcriptional Targeting 596
Mutation Compensation 597
Induction of Tumor Suppressor Genes 597
Pro-apoptotic and Cell Cycle Gene Therapy 598
Inactivation of Oncogenes 598
Genetic Immunopotentiation 599
Genetic Modifi cation of Tumor Cells 599
Genetic Modifi cation of Immune Effector Cells 599
Molecular Chemotherapy 599
Evolution of Molecular Chemotherapy Paradigm 599
From Concept to Clinical Trials 600
Inhibition of Angiogenesis 603
Replicative Vector Oncolysis 605
Chemosensitization and Radiosensitization 607
Current Limitations and Future Directions of Cancer Gene Therapy 608
References 609
Chapter 20 617
Regulatory process for approval of biologicals for cancer therapy 617
The Doctor–Patient Relationship: Duty and Responsibility 617
Development of Cancer Therapeutics 618
Biologicals and the Treatment of Cancer 620
Rationale for Developing Biological Therapies 620
Rituximab as an Example 620
The USA’s Food and Drug Administration 623
The Oncologic Drugs Advisory Committee of the FDA 624
Regulatory Review and Approval Process 625
Accelerated Versus Regular Approvals 625
Clinical Trial Endpoints 627
The FDA’s Track Record 628
Is there a Simpler Approach to the Development of New Therapies? A Proposal 629
Drug Development Versus Treatment Development 629
Kinds of Useful Anticancer Agents 630
Conclusions 631
Curing Cancer 631
The Patient’s Plight 632
What does the Future Hold? 632
References 632
Chapter 21 634
Cancer biotherapy: 2009 disease-related activity 634
References 635
Chapter 22 636
Biological therapy of melanoma 636
Melanoma and the Immune System 636
Biotherapy of Malignant Melanoma 636
Immunostimulation and Vaccines 637
Interferon 638
Interleukin 2/lymphokineactivated Killer (LAK) Cells 640
Interleukin 2/T-cells 641
Gene therapy 642
Antibodies 643
References 644
Chapter 23 648
Biological therapy of genitourinary cancer 648
Kidney Cancer 648
Overview 648
Cytotoxic Chemotherapy is Ineffective 648
Kidney Cancer is Responsive to the Immune System 648
Cytokine Therapy 650
Interferon-alpha 650
PEG-interferon 652
Other Interferons 652
Cytokine Combinations 654
Adoptive Cellular Therapy 655
Allogeneic Stem Cell Transplantion 655
Vaccines and Gene Therapy 656
Targeted therapy 657
References 658
Chapter 24 662
Biological therapy of colon cancer 662
Colon Cancer 662
Non-specific Immune Stimulants 662
Levamisole 662
Thymosin Fraction 5 663
Interferons 663
Interleukin-2 664
Adoptive Cell Therapy 664
Monoclonal Antibodies 664
Chapter 25 672
Biological therapy of breast cancer 672
Breast Cancer 672
Non-specifi c Immune Stimulation 672
Bacillus Calmette Guerre (BCG) 672
Corynbacterium Parvum 672
Pseudomonas Antigens 672
Levamisole 673
Poly A:U 673
Immunoactivation/Absorption/ Ultrafi ltration 673
Cytokines 674
Interferon 674
Interleukin-2 674
Retinoids 675
Cis-retinoic Acid 675
Bexarotene 675
Monoclonal Antibodies 675
Trastuzumab 675
Vaccines 678
References 678
Chapter 26 682
Biological therapy of lung cancer 682
Non-specifi c Immunostimulants 682
Bacillus Calmette Guerin (BCG) 682
Corynebacterium Parvum 682
Levamisole 683
OK-432 683
Thymic Hormones 683
Interferon alpha 684
Retinoids 685
Prevention Trials 685
Cis-retinoic Acid and Interferon 686
Cis-retinoic Acid and Chemotherapy 686
Trans-retinoic Acid and Interferon 686
Transretinoic Acid and Chemotherapy 686
Interferon Gamma 687
Non Small Cell Lung Cancer 687
Small Cell Lung Cancer 687
Interleukin-2 Alone, in Combination, or with Adoptive Cellular Therapy 687
IL-2 in NSCLC 687
IL-2 in SCLC 687
IL-2 and LAK 688
IL-2 and TIL 688
Interleukin-4 688
Amifostine (Ethyol™) 688
Monoclonal Antibodies 689
Vaccines 690
Summary 690
References 690
Chapter 27 695
Biological therapy of B and T cell lymphoproliferative disorders 695
Hairy Cell Leukemia 695
B Cell Lymphoma 695
Interferon 695
Interleukin-2 697
Monoclonal Antibodies 698
Immunotoxins 700
Vaccines 700
T Cell Lymphoproliferative Malignancies 701
Interferon 701
Interleukin-2 703
Retinoids 703
Immunotoxins 703
Monoclonal Antibodies 703
Vaccines 703
Summary 704
Chronic Lymphocytic Leukemia 704
Interferon 704
Monoclonal Antibodies 704
Summary 705
References 706
Chapter 28 712
Biological therapy of multiple myeloma 712
Interferon 712
Antibodies 712
References 712
Chapter 29 714
Biological therapy of squamous cell cancers of the head and neck 714
Introduction 714
Non-specifi c Immune Stimulants 714
Bacillus Calmette Guerin (BCG) 714
Levamisole 714
Cornybacterium Parvum (C parvum) 715
OK-432 715
Thymic Hormones 715
Interferons 716
Interferon-Alpha 716
Interferon-gamma 716
Interleukins 716
Interleukin-2 716
Interleukin-12 717
Retinoids and Vitamins 717
Vaccines 719
Adoptive Cell Therapy 719
Antibody Therapy 719
Summary 720
References 720
Chapter 30 723
Biological therapy of glioblastoma 723
Current Status of Therapy for Glioblastomas 723
Biological Therapy of Glioblastoma 723
Non-specifi c Immune Stimulators 724
Interferons 724
Interferon-alpha 724
Interferon-beta 725
Interferon-gamma (IFN-Gamma) 725
Retinoids 725
Adoptive Cell Therapy 726
Intravenous adoptive cell therapy approaches 726
Localized Adoptive Cell Therapy Approaches 726
Antibody Therapy 728
Vaccine Therapy 729
Summary 729
References 729
Chapter 31 733
Speculations for 2009 and beyond 733
Beyond Interferon 734
Lymphokines/cytokines 734
Antigen-specifi c Lymphokines 734
Growth and Differentiation Factors 734
Monoclonal Antibodies 735
Cancer Treatment: The Future 736
Biotherapy is not Chemotherapy and it not just Immunotherapy 736
References 738
Index 739