Principles of Cancer Biotherapy

ASD......Page 2
Preface......Page 5
Contents......Page 7
Contributors......Page 9
Historical Perspectives......Page 12
Evaluation of Screening Programs......Page 15
Nonspecific Immunomodulators......Page 16
Active Specific Immunotherapy......Page 17
Recombinant DNA Technology......Page 18
Lymphokines/Cytokines......Page 19
Interferons......Page 20
Growth and Maturation Factors......Page 21
Monoclonal Antibodies......Page 23
References......Page 24
The Pathogenesis of Cancer Metastasis......Page 28
Neovascularization-Angiogenesis......Page 29
Lymphatic Metastasis......Page 31
Hematogenous Metastasis......Page 32
The Biologic and Metastatic Heterogeneity of Neoplasms......Page 33
Clonal Origin of Cancer Metastases......Page 34
Development of Biological Diversity within and Among Metastases......Page 35
Zonal Heterogeneity for Gene Expression......Page 36
Tumor-Organ Interaction: The “Seed and Soil” Hypothesis......Page 37
Regulation of Tumor Cell Gene Expression by the Organ Microenvironment......Page 38
Regulation of Angiogenesis by the Organ Microenvironment......Page 39
Regulation of Response to Chemotherapy by the Organ Microenvironment......Page 40
Targeting the Expression of Platelet-Derived Growth Factor Receptor by Reactive Stroma......Page 41
Targeting Platelet-Derived Growth Factor Receptor on Endothelial Cells of Multidrug Resistant Prostate Cancer......Page 43
References......Page 45
Developmental therapeutics and the design of clinical trials......Page 52
Drug Development......Page 53
Biologicals and BRM Development......Page 55
Biotherapy Trial Strategies......Page 56
Escalating-dose Trials within Individual Patients......Page 57
Route......Page 58
Future Prospects......Page 59
References......Page 61
Isolation, Cloning and Expression of Genes......Page 64
Recombinant Proteins as Cancer Therapeutics......Page 67
Interferons......Page 68
Interleukins......Page 71
Colony-Stimulating Factors......Page 73
Tumor Necrosis Factors......Page 74
Soluble Cytokine Receptors......Page 75
Genomics and Proteomics in Cancer Therapeutic......Page 76
cDNA Arrays are Dotted Arrays of PCR Amplified Products of Cloned Genes......Page 77
Antibodies and Conjugates......Page 78
Monoclonal Antibodies-Conjugated Drugs......Page 79
Immunotoxins......Page 80
Cancer Vaccines......Page 82
Problems Unique to Recombinant Biotherapeutics......Page 84
Delivery of Therapeutic Proteins......Page 85
References......Page 86
Current Concepts of Immunity......Page 95
T lymphocytes......Page 98
T-suppressor Cells......Page 100
B lymphocytes......Page 101
Natural Killer Cells......Page 102
Delayed Type Hypersensitivity (DTH)......Page 103
Lymphoproliferative Responses......Page 104
Immunoregulatory Cell Functions......Page 105
References......Page 106
Immunosuppression and Cancer......Page 110
Effector Cell Numbers and Function......Page 111
Immunoregulatory Cells......Page 112
Immunomodulatory Factors......Page 113
Lymphoproliferative Responses (LPR)......Page 114
Cytolytic Functions......Page 115
Hematopoietic Malignancies......Page 116
Solid Tumors......Page 117
Perioperative Blood Transfusion......Page 118
Radiation Therapy-induced Immunosuppression......Page 119
Antimetabolites......Page 120
Antitumor Antibiotics......Page 121
Combination Chemotherapy......Page 122
Hematopoietic Malignancies......Page 123
Chemicals......Page 124
Histamine Receptor Antagonists......Page 125
Thymic Factors......Page 126
T-cell Reconstituting Factor......Page 127
Retinoids......Page 128
Hodgkin’s Disease......Page 129
Malignant Melanoma......Page 130
Gynecologic and Urologic Cancer......Page 131
Levamisole......Page 132
Prostaglandin Antagonists......Page 133
Retinoids......Page 134
Levamisole......Page 135
Adjuvant Chemotherapy......Page 137
Current Status of Therapeutic Alterations for Cancer-associated Immune Suppression......Page 138
References......Page 139
Approaches to Cancer Vaccines......Page 155
Pitfalls in Developing Cancer Vaccines......Page 156
Therapeutic Cancer Vaccines......Page 157
Conclusion......Page 159
References......Page 160
Cytokine Receptors: Many Belong to Receptor Families......Page 162
The Helper T Cell System......Page 170
Inflammation, Immune Regulation, Hematopoiesis, and Wound Repair......Page 172
Growth And Activation of T, B and NK Cells; Activation-Induced Cell Death; Elimination of Self-Reactive T Cells......Page 176
Hematopoietic Cytokine......Page 178
B Cell and T Helper Response......Page 179
Hematopoiesis, Thrombopoiesis, Inflammation......Page 181
T Cell, B Cell, Macrophage and Dendritic Cell Development......Page 184
Chemotaxis, Angiogenesis......Page 186
Regulator of Immune Response......Page 187
Hematopoietic Progenitor/Thrombocytosis Stimulator; Regulator of Inflammation......Page 189
Immune Stimulation, Inflammation, Hematopoiesis, Regulator of Innate and Adaptive Immunity......Page 190
Regulation of Inflammation; Allergy......Page 192
NK Cell Activity, Maintenance of T Cell Memory......Page 193
Chemoattractive; Proinflammatory; Immunoregulatory; Anti-HIV......Page 194
Proinflammatory, Hematopoietic, Neutrophil Development......Page 196
Proinflammatory Cytokine......Page 197
Interferon Gamma, NK and Th1 Response, Regulation of Inflammation......Page 198
Inflammation......Page 200
NK, T and B Cell Development, Immunomodulation......Page 201
T cell Stimulation, Inflammation, Regulator of Adaptive and Innate Immunity......Page 202
Proinflammatory; Regulation of Th17......Page 203
Type III Interferons; Antiviral, Antitumor......Page 204
Inflammation, Allergy......Page 205
Costimulation of T Cells, T Cell Memory......Page 206
T Cell Costimulation, Selection; Apoptosis; Regulation of Ig Class Switching......Page 207
Costimulatory, Proinflammatory; B, and T Cell Stimulation......Page 208
Cell Activation, Migration, and Recruitment; Inflammation; Angiogenesis......Page 210
Stimulator of Early Hematopoietic Stem Cells and Dendritic Cells......Page 211
T Cell Development, Regulator of Inflammation, Embryonic Development......Page 213
Lymphoid Organogenesis; Inflammation; T Cell, B Cell, Bone Cell Development......Page 214
Lymphoid Organogenesis; Inflammatory; NK, Dendritic Cell Development......Page 215
Lymph Node/T Cell Development; Inflammation; Growth and Wound Repair......Page 216
Pro Th1, Nitric Oxide Synthetase Inhibiting Cytokine......Page 217
Costimulation in T Cell, B Cell Development/Memory; Inflammation......Page 218
Early Progenitor and Mast Cell Growth Factor......Page 219
Inflammation, Immune Regulation, Apoptosis, Endothelial Damage......Page 220
Cell Growth, Survival; Angiogenesis; Inflammation......Page 223
References......Page 224
Abbreviations......Page 283
Nomenclature......Page 284
Hairy Cell Ieukemia......Page 286
Multiple Myeloma......Page 287
Non-Hodgkin’s lymphoma (NHL)......Page 288
Chronic Myeloid leukemia (CML)......Page 291
Interferon in combination with cytotoxic drugs in the treatment of CML......Page 292
Kaposi’s Sarcoma......Page 293
Adjuvant Therapy......Page 294
Renal Carcinoma......Page 295
Other Solid Tumors......Page 296
Antiviral Activity......Page 297
Immune Modulation......Page 298
Anti-Angiogenesis......Page 299
References......Page 300
Historical aspects 1900–1980......Page 309
Human Trials with Murine Monoclonal Antibodies 1980–1989......Page 311
Antibodies and Antigens......Page 312
Hybridoma Technology......Page 313
Human Monoclonal Antibodies......Page 315
Chimeric and Humanized Monoclonal Antibodies......Page 316
Mechanisms of Antibody-Mediated Anti-Tumor Effects......Page 317
Antibody Dependent Cell-Mediated Cytotoxicity......Page 318
Idiotype Network......Page 319
Epidermal Growth Factor and its Receptors (EGF and EGFR)......Page 320
In Vivo Binding to Malignant Cells......Page 321
Clinical Effi cacy and Mechanisms......Page 322
Adverse Events: Toxicity and side Effects......Page 323
Infusion Reactions......Page 324
Tumor lysis Syndrome......Page 325
Side Effects Secondary to Binding to Non-Malignant Tissues......Page 326
Human Anti-Immunoglobulin Response......Page 327
Antigenic Modulation......Page 328
Antibody Dose......Page 329
Serum Levels and Pharmacokinetics......Page 330
Rituximab and CD20......Page 331
Rituximab in Follicular Lymphoma......Page 332
Rituximab in Marginal Zone Lymphoma......Page 333
Rituximab in Mantle Cell Lymphoma......Page 334
Rituximab in Multiple Myeloma......Page 335
Extended therapy and Maintenance Rituximab......Page 336
Indolent and Follicular Lymphoma......Page 338
Large B Cell Lymphoma......Page 339
Mantle Cell lymphoma......Page 341
HIV Associated Lymphoma......Page 342
Maintenance Rituximab following Chemotherapyor Rituximab Plus Chemotherapy......Page 343
Rituximab with other monoclonal antibodies......Page 344
Summary......Page 345
Clinical Trials with Alemtuzumab......Page 346
Summary......Page 348
Trastuzumab and Her2......Page 349
Trastuzmab Alone......Page 350
Combination Chemotherapy and Trastusumab......Page 351
Randomized Trials of Chemotherapy With or Without Trastuzumab in Breast Cancer......Page 352
Adjuvant Treatment of Breast Cancer......Page 353
Trastuzumab in Other Tumor Types......Page 354
Toxicity and Side Effects......Page 355
Bevacizumab and Vascular Endothelial Growth Factor......Page 356
Clinical Trials with Bevacizumab......Page 357
Cetuximab and the Epidermal Growth Factor Receptor......Page 362
Clinical Trials with Cetuximab......Page 363
Mechanisms of Anti-Tumor Activity and Toxicity......Page 366
Clinical Trials with Panitumumab......Page 367
Toxicities......Page 368
Anti-Idiotype Antibodies......Page 369
CD3......Page 370
CD5......Page 371
CD20......Page 372
CD25......Page 373
CD30......Page 374
CD45......Page 375
Anti CTLA4 (Cytotoxic T Lymphocyte Antigen 4)......Page 376
Tumor Necrosis Factor-Related Apoptosis- Inducing Ligand (Trail) Receptor......Page 377
Human Epidermal Growth Factor Receptor Antigens (EGFR1)......Page 378
Human Epidermal Growth Factor Receptor Antigens (EGFR2)......Page 379
Transferrin Receptor......Page 380
Epithelial Cell Adhesion Molecule (EpCAM)......Page 381
Other Anti-Adenocarcinoma Monoclonal Antibodies......Page 384
Melanoma and Neuroectodermal Associated Antigens......Page 386
Other Ligand Targets......Page 389
Anti-Idiotype Vaccines in Adenocarcinomas......Page 390
References......Page 391
Type I plant A-B Toxins......Page 413
Type I plant A toxins......Page 414
Type I Bacterial A-B Toxins......Page 415
Type I Bacterial Binary Toxin......Page 419
Type I Vertebrate A Toxins......Page 420
Type III Toxins......Page 421
Ligand Selection......Page 422
Preclinical Studies with Immunotoxins......Page 432
Effi cacy......Page 433
Toxicities......Page 435
Ongoing and Future Clinical Studies......Page 436
References......Page 437
The Problem of Heterogeneity: Antibody-Based Therapeutics as a Solution......Page 456
Rationale for Immunoconjugates......Page 457
Rationale for Antitumor Cocktails......Page 458
Pre-Clinical Studies......Page 460
Clinical Trials......Page 462
References......Page 464
Radionuclides for Radioimmunotherapy......Page 468
Beta Particle Decay......Page 469
Antibody-Based Radiopharmaceuticals......Page 470
Lymphoma......Page 471
131I-Tositumomab......Page 472
90Y-ibritumomab tiuxetan......Page 473
High-dose Radioimmunotherapy with Stem Cell Support for Lymphoma......Page 474
Beta emitting Radionuclides for RIT of Leukemia......Page 475
Alpha Emitting Radionuclides for RIT of Leukemia......Page 476
Prostate Cancer......Page 477
Breast Cancer......Page 478
Systemic Injection......Page 479
Intrathecal......Page 480
Regulatory Peptides and their Receptors......Page 481
Radiolabeling of Peptides......Page 482
Clinical Experience with Somatostatin Analogs......Page 483
Gastrin......Page 484
Peptide Receptor Radionuclide Therapy (PRRT)......Page 486
Strategies to Improve Outcome of RIT......Page 487
Compartmental Administration......Page 488
Increasing the Dose Rate......Page 489
Reducing the Exposure to Normal Tissues......Page 490
Pretargeted RIT......Page 491
Pretargeted RIT for Lymphoma and Leukemia......Page 492
Summary......Page 493
References......Page 494
Autologous Bone Marrow Transplantation......Page 502
Ex vivo Purging with Chemotherapy......Page 503
Stem-cell Selection......Page 504
Graft-versus-tumor Effects......Page 505
References......Page 506
A Recap of where the Field has been......Page 510
Use of LAK and TIL in the Treatment of Cancer, are they gone Forever?......Page 512
Lymphocyte Defined Tumor Associated Antigens (LDTAs)......Page 514
Cancer Vaccines......Page 515
Dendritic Cells and Vaccines......Page 518
Treg Cells in Cancer: Biology and Potential Role in Tumor Immunity......Page 520
Immunological Monitoring......Page 521
Summary......Page 522
References......Page 523
Growth and differentiation factors as cancer therapeutics......Page 532
Human Leukemic Cell Lines as Models for Differentiation Therapy......Page 533
Vitamin A Analogues as Leukemia Differentiation-Inducing Agents......Page 537
Action of Vitamin D Metabolites on Cancer Cells......Page 545
Receptors for Vitamin D and its Metabolites......Page 548
In vivo Effects of Vitamin D Metabolites......Page 549
Polar-Planar Compounds as Differentiation Inducers......Page 551
Chemotherapeutic Agents as Differentiation Inducers......Page 552
In vivo Induction of Differentiation with low-dose Cytosine Arabinoside or Azocytidine in Patients with acute Myeloid Leukemia and Myelodysplastic Syndrome (MDS)......Page 553
Cytokines and Hematopoietic Growth Factors active in Regulating Proliferation and Differentiation of Leukemic Hematopoietic Cells......Page 554
CSF-Dependence of Myeloid Leukemic Progenitors......Page 555
Colony-Stimulating Factors as Leukemia Differentiating Agents......Page 556
Interleukin-6 and Leukemic Cell Proliferation and Differentiation......Page 557
Leukemia Inhibitory Factor......Page 558
Tumor Necrosis Factor (TNFAlpha) and Lymphotoxin (TNFBeta)......Page 559
Transforming Growth Factor Beta......Page 560
References......Page 562
Biochemistry and Structure......Page 574
Physiology......Page 577
Patients with Disease......Page 578
Chemotherapy-induced Neutropenia......Page 579
Bone Marrow or Stem Cell Transplantation......Page 580
Immunomodulation......Page 581
References......Page 582
Physiology......Page 586
Pharmacodynamics andPharmacokinetics......Page 587
Bone Marrow Failure States......Page 588
Immunomodulation......Page 589
References......Page 590
Gene Transfer Vectors......Page 594
Retroviral Vectors......Page 595
Herpes Simplex Virus......Page 596
Transcriptional Targeting......Page 597
Induction of Tumor Suppressor Genes......Page 598
Inactivation of Oncogenes......Page 599
Evolution of Molecular Chemotherapy Paradigm......Page 600
From Concept to Clinical Trials......Page 601
Inhibition of Angiogenesis......Page 604
Replicative Vector Oncolysis......Page 606
Chemosensitization and Radiosensitization......Page 608
Current Limitations and Future Directions of Cancer Gene Therapy......Page 609
References......Page 610
The Doctor–Patient Relationship: Duty and Responsibility......Page 618
Development of Cancer Therapeutics......Page 619
Rituximab as an Example......Page 621
The USA’s Food and Drug Administration......Page 624
The Oncologic Drugs Advisory Committee of the FDA......Page 625
Accelerated Versus Regular Approvals......Page 626
Clinical Trial Endpoints......Page 628
The FDA’s Track Record......Page 629
Drug Development Versus Treatment Development......Page 630
Kinds of Useful Anticancer Agents......Page 631
Curing Cancer......Page 632
References......Page 633
Cancer biotherapy: 2009 disease-related activity......Page 635
References......Page 636
Biotherapy of Malignant Melanoma......Page 637
Immunostimulation and Vaccines......Page 638
Interferon......Page 639
Interleukin 2/lymphokineactivated Killer (LAK) Cells......Page 641
Interleukin 2/T-cells......Page 642
Gene therapy......Page 643
Antibodies......Page 644
References......Page 645
Kidney Cancer is Responsive to the Immune System......Page 649
Interferon-alpha......Page 651
Other Interferons......Page 653
Cytokine Combinations......Page 655
Allogeneic Stem Cell Transplantion......Page 656
Vaccines and Gene Therapy......Page 657
Targeted therapy......Page 658
References......Page 659
Levamisole......Page 663
Interferons......Page 664
Monoclonal Antibodies......Page 665
Pseudomonas Antigens......Page 673
Immunoactivation/Absorption/ Ultrafi ltration......Page 674
Interleukin-2......Page 675
Trastuzumab......Page 676
References......Page 679
Corynebacterium Parvum......Page 683
Thymic Hormones......Page 684
Interferon alpha......Page 685
Prevention Trials......Page 686
Transretinoic Acid and Chemotherapy......Page 687
IL-2 in SCLC......Page 688
Amifostine (Ethyol™)......Page 689
Monoclonal Antibodies......Page 690
References......Page 691
Interferon......Page 696
Interleukin-2......Page 698
Monoclonal Antibodies......Page 699
Vaccines......Page 701
Interferon......Page 702
Vaccines......Page 704
Monoclonal Antibodies......Page 705
Summary......Page 706
References......Page 707
References......Page 713
Levamisole......Page 715
Thymic Hormones......Page 716
Interleukin-2......Page 717
Retinoids and Vitamins......Page 718
Antibody Therapy......Page 720
References......Page 721
Biological Therapy of Glioblastoma......Page 724
Interferon-alpha......Page 725
Retinoids......Page 726
Localized Adoptive Cell Therapy Approaches......Page 727
Antibody Therapy......Page 729
References......Page 730
Speculations for 2009 and beyond......Page 734
Growth and Differentiation Factors......Page 735
Monoclonal Antibodies......Page 736
Biotherapy is not Chemotherapy and it not just Immunotherapy......Page 737
References......Page 739
Index......Page 740