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Preclinical Models and Clinical Situation 43 Table 3 Selected Mechanisms of Immune Suppression in Tumor-Bearing Hosts and Intervening Strategies Preclinical evidence for synergy with cancer vaccines (selected examples) Reference Form of immunosuppression Therapeutic agent Mechanism of action See text 91–94 See text 95–100 Cyclophosphamide Induces apoptosis in Tregs and/or downregulation of GITR and FoxP3 gene expression Ontak Binds to high-affinity IL-2 receptor expressed on Tregs; death by intracellular Accumulation of CD4 þ CD25 þ regulatory T cells (Tregs) expressing GITR and FoxP3 ? reduces effector T cell function 101–103 Mice with 4–5 mm C3 or 3–5 mm Meth A fibrosarcomas treated with tumor-specific peptide in CFA or DCs transduced with p53, respectively þ implanted ATRA pellet: tumor size reduced 3–5-fold vs. accumulation of toxin Induces differentiation of ImCs; restores “normal” myeloid dendritic cell/ plasmacytoid dendritic cell ratio All-trans-retinoic acid (ATRA) Accumulation of immature myeloid cells (ImCs) ? loss of TCR x chain; block production of IFN-g by T cells 104 control No published studies testing MT1 in combination with cancer vaccines. Competitive inhibitor of IDO, thus preventing tryptophan catabolism 1-methyl-tryptophan (1MT) Elevated levels of indoleamine 2,3-dioxygenase (IDO) in APCs and tumor cells that degrades tryptophan ? effector T cell anergy/ apoptosis (Continued)
44 Levey Table 3 Selected Mechanisms of Immune Suppression in Tumor-Bearing Hosts and Intervening Strategies (Continued ) Preclinical evidence for synergy with cancer vaccines (selected examples) Reference Form of immunosuppression Therapeutic agent Mechanism of action 105–111 Tumor growth slower and metastases reduced in Met129 breast tumor– bearing mice partially depleted of B cells with anti-IgG/IgM sera; prolonged survival in transgenic B cell–deficient mice bearing B16 tumors vaccinated with adenovirus encoding TRP-2 compared with tumor–bearing w.t. Deplete B cells to eliminate their deleterious effects on anti-tumor immunity Rituxan or other B cell–depleting antibodies B cell production of CCL4 ? recruits CD4 þ CD25 þ Tregs; B cell–DC interaction ? promotes IL-4, IL-10 production 112–116 control mice 83% long–-term survival (80 days) in B16 tumor bearing mice injected with autologous HSP70 based vaccine in combination with gene encoding soluble PD-1 vs. 0% survival in controls Prevent effector T cell downregulation upon infiltration into tumor bed Blockade with anti-PD-1 or anti-B7-H1 antibodies; complete binding with soluble PD-1 B7-H1 expression on tumors ? interacts with PD-1 on effector T cells ? inhibits T cell proliferation and cytokine secretion
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Translational Medicine Series 6 Can
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TRANSLATIONAL MEDICINE SERIES 1. Pr
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Informa Healthcare USA, Inc. 52 Van
Page 8 and 9: Preface Throughout the last 20 year
Page 10 and 11: Preface vii Table 1 A Diverse Techn
Page 12 and 13: Preface . . . . v Contributors . .
Page 14 and 15: Contributors Pedro Alves Ludwig Ins
Page 16 and 17: 1 Factoring in Antigen Processing i
Page 18 and 19: Factoring in Antigen Processing in
Page 46 and 47: 2 Outlining the Gap Between Preclin
Page 48 and 49: Preclinical Models and Clinical Sit
Page 50 and 51: Table 1 Examples of Preclinical Act
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94 Luptrawan et al. ability of TIL
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96 Luptrawan et al. Figure 4 Drug s
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98 Luptrawan et al. Figure 6 Tumor
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Table 1 Summary of results of phase
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102 Luptrawan et al. Table 1 Summar
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104 Luptrawan et al. antigens (84,8
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106 Luptrawan et al. 30. Ranges GE,
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108 Luptrawan et al. 66. Dunn GP, B
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110 Schroter and Minev proteins (2,
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112 Schroter and Minev tumor-challe
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114 Schroter and Minev Table 1 Inve
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116 Schroter and Minev Table 1 Inve
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118 Schroter and Minev demonstrated
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120 Schroter and Minev loaded MART-
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122 Schroter and Minev illustrate t
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124 Schroter and Minev 4. Heemels M
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126 Schroter and Minev 42. Minev BR
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128 Schroter and Minev 74. Restifo
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7 Multimodality Immunization Approa
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Multimodality Immunization Approach
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Figure 5.1 Immunohistochemical char
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Figure 8.5 A schematic representati
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8 Bidirectional Bedside Lab Bench P
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Development of Novel Immunotherapeu
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9 Diagnostic Approaches for Selecti
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Diagnostic Approaches to Maximize T
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206 Index Antigenic peptides degrad
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208 Index Chromogens, enzymatic act
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210 Index Freund’s adjuvants. See
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212 Index Langerhans cells, 133, 13
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214 Index [Peptide vaccines] invest
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216 Index TCRL. See TCR-like immuno
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Oncology and Immunology about the b
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