Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

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achieve this is to arm antibodies that target cancer cells with powerful toxins that can originate from both plants and bacteria. The molecules generated are termed recombinant immunotoxins. The goal of immunotoxin therapy is to target a very potent cytotoxic agent to cell surface molecules which will internalize then the cytotoxic agent, resulting in cell death. Developing this type of therapy has gained much interest in recent years. Since immunotoxins differ greatly from chemotherapy in their mode of action and toxicity profile, it is hoped that immunotoxins will have the potential to improve the systemic treatment of tumors incurable with existing modes of therapy. As shown in Fig. 17.1, immunotoxins can be divided into two groups: chemical conjugates (or first-generation immunotoxins) and second-generation (or recombinant) immunotoxins. They both contain toxins that have their cell-binding domains either mutated or deleted to prevent them from binding to normal cells and are either fused or chemically conjugated to a ligand or an antibody specific for cancer cells (Tab. 17.1). This chapter will summarize our current understanding of the design and application of second-generation recombinant Fv±immunotoxins, which utilize recombinant antibody fragments as the targeting moiety, in the treatment of cancer, and will also discuss briefly the use of recombinant antibody fragments for other modes of cancer therapy and diagnosis. Tab. 17.1 Examples of recombinant immunotoxins against cancer 17.1 Introduction Immunotoxin Antigen Toxin Cancer Clinical trial Reference Anti-CD7±dgA CD7 ricin non-Hodgkin's lymphoma phase I 191 DAB 389±IL-2 IL-2 receptor DT T cell lymphoma, phase III 136, 139 Hodgkin's disease Anti-Tac (Fv)±PE38 CD25 PE B and T lymphoma, phase I 80, 95 (LMB-2) leukemias DT±anti-Tac(Fv) CD25 DT leukemias, lymphoma ± 91 RFB4(dsFv)±PE38 CD22 PE B leukemias phase I 90 Di-dgA±RFB4 CD22 ricin leukemias, non-Hodgkin's ± 98 lymphoma B3±lysPE38 (LMB-1) LeY PE carcinomas phase I 103 B3(Fv)±PE38 (LMB-7) LeY PE carcinomas phase I 81 B3(dsFv)±PE38 LeY PE carcinoma phase I 88 (LMB-9) BR96(sFv)±PE40 LeY PE carcinoma ± 109 e23(Fv)±PE38 erbB2/HER2 PE breast cancer phase I 82 FRP5(scFv)ETA erbB2/HER2 PE breast cancer ± 110 Tf±CRM107 transferrin DT glioma phase I 117 receptor HB21(Fv)±PE40 transferrin PE various ± 69 receptor MR1(Fv)±PE38 mutant EGF PE liver, brain tumors ± 113 receptor SS1(Fv)±PE38 mesothelin PE ovarian cancer ± 114 349
350 17 Immunotoxins and Recombinant Immunotoxins in Cancer Therapy 17.2 First-and Second-Generation Immunotoxins First-generation immunotoxins were made in the early 1970s and were composed of cancer-specific monoclonal antibodies (mAbs) to which native bacterial or plant toxins were chemically conjugated. The understanding of toxin structure±function properties, and the advancement in recombinant DNA technology and antibody engineering lead to important breakthroughs in the late 1980s to construct second-generation recombinant immunotoxins that are composed of recombinant antibody fragments derived from cancer-specific antibodies or phage-display libraries and truncated forms of toxins. These molecules are produced in large amounts, needed for preclinical and clinical studies, in bacteria and feature better clinical properties. As shown in Fig. 17.1, first- and second-generation immunotoxins contain toxins that have their cell-binding domains either mutated or deleted to prevent them from binding to normal cells, and are either chemically conjugated or fused to a ligand or an antibody specific for cancer cells. First-generation immunotoxins, composed of whole antibodies chemically conjugated to toxins, demonstrated the feasibility of this concept. Cancer cells cultured in vitro could be killed under conditions in which the immunotoxin demonstrated low toxicity towards cultured normal cells. Clinical trials with these agents had some success; however, they also revealed several problems, such as non-specific toxicity towards some normal cells, difficulties in production and, particularly for the treatment of solid tumors, poor tumor penetration due to their large size. Second-generation immunotoxins have overcome many of these problems. Progress in the elucidation of the toxin's structure and function combined with the techniques of protein engineering facilitated the design and construction of recombinant molecules with a higher specificity for cancer cells and reduced toxicity to normal cells. At the same time, advances in recombinant DNA technology and antibody engineering enabled the generation of small antibody fragments. Thus, it was possible to decrease the size of immunotoxins significantly and to improve their tumor-penetration potential in vivo. The development of advanced methods of recombinant protein production enabled the large-scale production of recombinant immunotoxins of high purity and quality for clinical use in sufficient quantities to perform clinical trials. Another strategy to target cancer cells is to construct chimeric toxins in which the engineered truncated portion of the toxin [Pseudomonas exotoxin (PE) or diphtheria toxin (DT)]gene is fused to cDNA encoding growth factors or cytokines. These include transforming growth factor (TGF)-b [18], insulin-like growth factor (IGF)-1 [19], acidic and basic fibroblast growth factor (FGF) [20], IL-2 [21], IL-4 [22], and IL-6 [23]. These recombinant toxins (oncotoxins) are designed to target specific tumor cells that over-express these receptors (Fig. 17.1). In the following sections we will summarize the rationale and current knowledge on the design and application of second-generation recombinant Fv±immunotoxins, which utilize recombinant antibody fragments as the targeting moiety. Recent results of clinical trials are summarized. We will also discuss the powerful new technologies for selecting new antibodies with unique specificities and improved properties.
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Cancer Immune Therapie: Current and
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Editors: Dr. Gernot Stuhler Univers
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VI Preface Recent years have seen a
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VIII Contents 2.5.3 Antigens Encode
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X Contents 6.4.2 Natural Killer (NK
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XII Contents 9.6 Loading DC with An
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XIV Contents 14.2.2.1 Cancer-specif
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List of Contributors Richard Bucala
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Color Plates Fig. 5.2 The MHC class
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Fig. 5.5 Different immune effector
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Fig. 5.17 Possible pathway for the
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Fig. 6.2 T lymphocytes in the tumor
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Index a acidic and basic fibroblast
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±, see also tumors cationic lipids
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e EBV see Epstein-Barr virus EDR se
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immature Mo-DCs 184 immune cells ±
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MHC class I antigen-processing mach
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±, onco- 209 ±, over-expressed ce
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TICD see tumor-induced cell death T
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Part 1 Tumor Antigenicity Cancer Im
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4 1 Search for Universal Tumor-Asso
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10 1 Search for Universal Tumor-Ass
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18 2 Serological Determinants On Tu
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30 Cancer Immune Therapie: Current
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32 3 Processing and Presentation of
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42 4 T Cells In Tumor Immunity cult
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44 4 T Cells In Tumor Immunity cell
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46 4 T Cells In Tumor Immunity to T
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48 4 T Cells In Tumor Immunity Alth
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50 4 T Cells In Tumor Immunity Tab.
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52 4 T Cells In Tumor Immunity rest
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54 4 T Cells In Tumor Immunity 53 T
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Part 2 Immune Evasion and Suppressi
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60 5 Major Histocompatibility Compl
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68 Tab. 5.1 HLA class I loss attrib
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96 6 Immune Cells in the Tumor Micr
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98 6 Immune Cells in the Tumor Micr
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100 6 Immune Cells in the Tumor Mic
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Tab. 7.1 Effects of tumor-derived m
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122 7 Immunosuppresive Factors in C
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156 8 Interleukin-10 in Cancer Immu
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Part 3 Strategies for Cancer Immuno
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180 9 Dendritic Cells and Cancer: P
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206 10 The Immune System in Cancer:
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254 12 Principles and Strategies Em
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270 13 Applications of CpG Motifs f
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288 14 The T-Body Approach: Towards
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Page 415 and 416: 382 Glossary tion to the variable d
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