I would like to thank all my co-workers who have collaborated with me, from 1963 until now, in biological and clinical research in the field of cancer active immunotherapy, of its immuno­ prevention and immunorestoration. They will often be quoted in this book. I am particularly grateful to those who have helped me to write it by reviewing some chapters: D. BELPOMME, J. F. DOR~, IRENE FLORENTIN, A. GOUTNER, I. J. Hm, R. HUCHET and MARIE-CHRISTINE SIMMLER. I also thank NICOLE VRIZ, MARIE-CLAUDE SCHNEIDER, FENELLARIsELEY and M. JUVET for their willing and efficient co-operation in the preperation of the manuscript. I am finally grateful to all authors of books or articles who authorized me to reproduce their figures or tables. Paris, April 1976 G. MAT~ Contents Chapter 1. Introduction and Definitions 1 Chapter 2. Biological Basis: Tumour Associated Antigens, the Immune Machinery and Its Behaviour Concerning Cancer Cells 5 2. 1. Tumour-Associated Antigens 5 2. 2. The Immune Machinery 19 2. 2. 1. Humoral Mediated Immunity and Cell Mediated Immunity 19 2. 2. 2. T- and B-Lymphocyte and Monocyte Differen­ tiation 22 2. 2. 3. T-Lymphocyte Functions 25 2. 2. 4. B-Lymphocyte Functions 30 2. 2. 5. Macrophage Functions 31 2. 2. 6. K-Cell Function 32 2. 3. The Immune Machinery and Cancer Cells 33 2. 3. 1. Mechanisms Involved in Tumour Cell Rejec­ tion 33 2. 3. 1. 1. In vivo Evidence for Tumour Immunity 33 2. 3. 1. 2.

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1. Introduction and Definitions.- 2. Biological Basis: Tumour Associated Antigens, the Immune Machinery and Its Behaviour Concerning Cancer Cells.- 2.1. Tumour-Associated Antigens.- 2.2. The Immune Machinery.- 2.2.1. Humoral Mediated Immunity and Cell Mediated Immunity.- 2.2.2. T- and B-Lymphocyte and Monocyte Differentiation.- 2.2.3. T-Lymphocyte Functions.- 2.2.4. B-Lymphocyte Functions.- 2.2.5. Macrophage Functions.- 2.2.6. K-Cell Function.- 2.3. The Immune Machinery and Cancer Cells.- 2.3.1. Mechanisms Involved in Tumour Cell Rejection.- 2.3.1.1. In vivo Evidence for Tumour Immunity.- 2.3.1.2. In vitro Assays for Cell Mediated Immunity.- 2.3.1.3. Role of T-Lymphocytes in Tumour Rejection.- 2.3.1.4. Role of Antibody in Tumour Cell Rejection.- 2.3.1.5. Role of K-Cells.- 2.3.1.6. Role of Macrophages.- 2.3.2. Escape Mechanisms to Tumour Destruction.- 2.3.2.1. Escape Mechanisms Prior to Tumour Establishment.- 2.3.2.2. Escape Mechanisms after Tumour Establishment.- 2.3.2.2.1. Role of Serum Blocking Factors.- 2.3.2.2.2. Role of Suppressor Cells.- 2.3.2.2.3. Role of the Tumour Itself.- 2.3.3. The Immune Balance.- 3. Systemic Active Immunotherapy.- 3.1. Experimental.- 3.1.1. Leukaemias.- 3.1.1.1. Active Immunotherapy on Limited Tumour Cell Populations.- 3.1.1.2. Type of Action: The Plateau of Tumour Growth Phenomenon.- 3.1.1.3. Comparison of the Use of Sterilized Tumour Cells, a Systemic Immunity Adjuvant (BCG), or a Combination of Both.- 3.1.1.4. Active Immunotherapy after Cell Reduction by Chemotherapy.- 3.1.1.5. Immunotherapy and Immunological Parameters.- 3.1.1.6. Active Immunotherapy of Perceptible Voluminous Leukaemia.- 3.1.2. Solid Tumors.- 3.1.2.1. Active Immunotherapy on Limited Tumour Cell Population.- 3.1.2.2. Active Immunotherapy after Cell Reduction by Surgery and/or Radiotherapy and/or Chemo- or Hormonotherapy.- 3.1.2.3. Active Systemic Immunotherapy of Perceptible Voluminous Solid Tumours.- 3.1.2.4. Immunotherapy of Metastasis.- 3.1.3. Problems Common to Leukaemias and Solid Tumours.- 3.1.3.1. The Myth of Immunological Tolerance in the Case of Tumours Associated with Vertically Transmitted Spontaneous Virus.- 3.1.3.2. Immunotherapy and Chemotherapy Interspersed.- 3.1.3.3. Negative Results.- 3.1.3.4. The Possibility of Neoplasia Growth Enhancement.- 3.2. Clinical.- 3.2.1. Leukaemias and Hematosarcomas.- 3.2.1.1. Residual Imperceptible Disease.- 3.2.1.1.1. Acute Lymphoid Leukaemia.- 3.2.1.1.2. Acute Myeloid Leukaemia.- 3.2.1.1.3. Blastic Crisis of Chronic Myeloid Leukaemia.- 3.2.1.1.4. Lymphosarcomas.- 3.2.1.1.5. Hodgkin's Disease.- 3.2.1.2. Treatment of Perceptible Disease.- 3.2.1.2.1. Acute Lymphoid Leukaemia.- 3.2.2. Solid Tumours.- 3.2.2.1. Treatment of Residual Imperceptible Disease.- 3.2.2.1.1. Special Case of Placental Choriocarcinoma.- 3.2.2.1.2. Melanoma.- 3.2.2.1.3. Bronchus Cancer.- 3.2.2.1.4. Mammary Carcinoma.- 3.2.2.1.5. Osteosarcoma.- 3.2.2.2. Treatment of Perceptible Disease.- 3.2.2.2.1. Melanoma.- 3.2.2.2.2. Bronchus Cancer.- 3.2.2.2.3. Head and Neck Tumours.- 3.2.2.2.4. Gynaecological Cancers.- 3.2.2.2.5. Brain Tumours.- 3.2.2.2.6. Various Tumours.- 3.2.3. Problems Common to Leukaemia and Solid Tumours.- 3.2.3.1. Immunotherapy and Chemotherapy Interspersed.- 3.2.3.2. Negative Results.- 3.2.3.3. Possibility of Neoplasia Growth Enhancement.- 4. Cancer Local Active Immunotherapy.- 4.1. Experimental.- 4.1.1. BCG and Other Mycobacteria.- 4.1.2. Corynebacteria and Other Bacterias.- 4.1.3. Other Agents.- 4.1.4. Failures and Factors and Conditions of Efficacy.- 4.1.5. Possibility of Neoplasia Growth Enhancement.- 4.2. Clinical.- 4.2.1. BCG.- 4.2.2. Other Agents.- 4.2.3. Failures, Factors and Conditions of Efficacy.- 4.2.4. Possibility of Neoplasia Growth Enhancement.- 5. Towards Immunoprophylaxis.- 5.1. Experimental.- 5.1.1. Grafted Tumours.- 5.1.1.1. Use of Neoplastic Cells.- 5.1.1.2. Use of Systemic Immunity Adjuvants.- 5.1.1.3. Combination of an Adjuvant and of Tumour Cells.- 5.1.2. Carcinogen Induced and Spontaneous Tumours.- 5.1.2.1. Virus Induced Tumours.- 5.1.2.1.1. Use of Tumour Cells or Viruses.- 5.1.2.1.2. Use of Systemic Immunity Adjuvants.- 5.1.2.1.3. Use of a Combination of an Adjuvant and of Tumour Cells or Viruses.- 5.1.2.2. Chemically Induced Tumours.- 5.1.2.2.1. Use of Cells.- 5.1.2.2.2. Use of Systemic Immunity Adjuvants.- 5.1.2.3. Does Immunoprophylaxis Work before Carcinogenes is Established?.- 5.1.2.4. Failures.- 5.1.2.5. Possibility of Neoplasia Growth Enhancement.- 5.1.2.5.1. Grafted Tumours.- 5.1.2.5.2. Induced Tumours.- 5.2. Clinical.- 5.2.1. Prophylaxis of Blastic Crisis of Chronic Myeloid Leukaemia.- 5.2.2. Prophylaxis of Childhood Leukaemia by BCG Vaccination.- 6. Towards Immune Restoration.- 6.1. Immunodeficiency Associated with Cancer, and Cancer Risk in Immunodeficiency Subjects.- 6.1.1. Experimental.- 6.1.1.1. Animals with Cancer.- 6.1.1.2. Cancer Risk in Immunodeficient Animals.- 6.1.2. Clinical.- 6.1.2.1. Cancer Patients.- 6.1.2.1.1. Immunodeficiency Due to Treatments.- 6.1.2.1.2. Immunodeficiency Due to/or Associated with Cancer.- 6.1.2.2. Immunodeficiency Diseases or Syndromes with High Cancer Risk.- 6.2. Attempts at Immunorestoration.- 6.2.1. Experimental.- 6.2.1.1. Use of Thymic Lymphocyte-Stimulating Factor (or Thymosin).- 6.2.1.2. Use of Adjuvants.- 6.2.2.1. Transfer Factor.- 6.2.2.2. Thymus Lymphocyte Stimulating Factor (or Thymosin).- 6.2.2.3. Adjuvants.- 6.2.2.4. Immune "Restoration" by Proteolysis.- 6.2.2.5. Immunorestoration by Surgery.- 6.2.2.6. Immunorestoration by Cancer Chemotherapy.- 6.2.2.7. Combined Methods.- 7. Developmental Pharmacology.- 7.1. Systemic Specific Active Immunotherapy or Immunoprophylaxis.- 7.1.1. Tumour Cells and/or Antigens.- 7.1.1.1. Should Antigenicity be Restricted to Tumour-Associated Antigens or Not?.- 7.1.1.2. Allogeneic Versus Autologous Materials. Tumour Type Cells for Treated Tumour Types.- 7.1.1.3. Antigenicity and/or Immunogenicity.- 7.1.1.5. Division-Sterilized Cells.- 7.1.1.6. Cryopreserved Cells.- 7.1.1.7. Pooled Cells.- 7.1.1.8. Subpopulations of Cells.- 7.1.1.9. Living Versus Killed Cells.- 7.1.2.0. Modified Cells.- 7.1.2.1. Cultured Cells.- 7.1.2.2. Modified Normal Cells.- 7.1.2.3. Hybridized Cells.- 7.1.2.4. Tumour-Associated Antigen Preparations.- 7.1.2. Dose Factor.- 7.1.3. Sites of Administration.- 7.1.4. Should Cells or Antigens be Mixed with the Adjuvant?.- 7.2. Systemic Non-Specific Active Immunointervention.- 7.2.1. Systemic Immunity Adjuvants.- 7.2.1.1. The Innumerable Adjuvants in the Literature.- 7.2.1.2. Experi…