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

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15 Bone Marrow Transplantation for Immune Therapy Fabio Ciceri and Claudio Bordignon 15.1 Introduction Allogeneic bone marrow transplantation (BMT), now otherwise defined as hematopoietic cell transplantation (HCT), was initially considered for the treatment of malignancy as a means to deliver supralethal doses of chemotherapy and total body radiation [1±3]. Many malignancies exhibit a steep dose±response relationship to chemo- or radiotherapy, with higher doses producing greater cytoreduction. BMT allows escalation of doses of many agents beyond those producing severe bone marrow toxicity. The marrow transplant was considered a supportive care modality to restore hematopoiesis. It has become clear, however, that the high-dose therapy does not eradicate the malignancy in many patients and that the therapeutic benefit of allogeneic BMT is largely related to an associated immune-mediated graft-versus-malignancy effect. In the last few years, the focus has shifted away from attempts at eradicating malignant cells through high-dose chemoradiation therapy toward using immunocompetent cells transplanted with the donor's stem cells, or arising from them, to exert a potent graft-versus-tumor (GvT) effect. HCT is now definitely accepted as an immunotherapeutic approach, rather than solely a vehicle to deliver high-dose therapy [4]. 15.2 Graft-versus-Host (GvH)Reactions Cancer Immune Therapie: Current and Future Strategies Edited by G. Stuhler and P. Walden Copyright # 2002 Wiley-VCH Verlag GmbH & Co. KGaA ISBNs: 3-527-30441-X (Hardback); 3-527-60079-5 (Electronic) Two immunologic barriers must be crossed to establish successful HCT allografts. The first consists of host-versus-graft (HvG) rejection and the second is made up of GvH reactions. The immunosoppressive regimens used to overcome the HvG rejection are administered before transplantation and are integrated into the high-dose conditioning therapy. The regimens for overcoming GvH reactions deal with the grafted donor immune cells and, accordingly, these treatments are delivered after transplantation in order to prevent graft-versus-host disease (GvHD). This potentially lethal complication of HCToccurs in 30±50% of patients undergoing HLA-matched- 299
300 15 Bone Marrow Transplantation for Immune Therapy related allograft, despite standard immunosoppressive prophylaxis. Acute and chronic GvHD are commonly graded as outlined in Tabs 15.1±15.3. When GvHD occurs, immunosoppressive treatment is mandatory; in the case of steroid-resistant GvHD, the association of antithymocyte globulin, anticytokine monoclonal antibodies, mycophenolate and many others immunosoppressive agents is frequently unsatisfactory for the control of disease [5]. The direct effect of GvH tissues damage and infections secondary to immunosuppression, largely contribute to transplant-related mortality (TRM) [6]. Tab. 15.1 Clinical staging of acute GvHD Stage Skin Liver Gut 0 no rash bilirubin 2000 ml/day; desquamation and bullae pain or ileus Tab. 15.2 Glucksberg grade of acute GvHD Grade Organ stage (S= skin, G = gut, L = liver) Clinical performance 0 none S = 0, G = 0, L = 0 no decrease I mild S = 1±2, G = 0, L = 0 no decrease II moderate S = 1±3, G = 1 and/or L = 1 mild decrease III severe S = 2±3, G = 2±3 and/or L = 2±4 marked decrease IV life threatening S = 2±4, G = 2±4 and/or L = 2±4 extreme decrease Tab. 15.3 International Bone Marrow Transplant Registry GvHD severity index Code Maximum organ stage (S= skin, G = gut, L = liver) Index 0 S=0,G=0,L=0 0 1 S=1,G=0,L=0 A 2 S, G = 1 and/or L = 2; or G and/or L =1 B 3 S, G and/or L = 3 C 4 S, G and/or L = 4 D
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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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232 11 Hybrid Cell Vaccination for
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Page 281 and 282: 248 11 Hybrid Cell Vaccination for
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Page 303 and 304: 270 13 Applications of CpG Motifs f
Page 321 and 322: 288 14 The T-Body Approach: Towards
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350 17 Immunotoxins and Recombinant
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382 Glossary tion to the variable d
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384 Glossary suppressor gene produc
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386 Glossary press the proper recep
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388 Glossary gp96 See Chaperone. Gr
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390 Glossary cytes and addressing l
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392 Glossary T bodies are being tes
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